Human hairy (not glabrous skin) is equipped with a subgroup of C-fibers, the C-tactile (CT) fibers. Those do not mediate pain but affective aspects of touch. CT-fiber-activation reduces experimental pain if they are intact. In this pilot study we investigated pain modulating capacities of CT-afferents in CRPS.10 CRPS-patients  and 11 healthy controls  participated.CT-targeted-touch  was applied on hairy and glabrous skin on the affected and contralateral limb. Patients rated pleasantness of CT-targeted-touch (anchors: 1 “not pleasant”—4 “very pleasant”) twice daily on 10 days. Pain intensity (NRS: 0 “no pain” – 10 “worst pain imaginable”) was assessed before, 0, 30, 60 and 120 min after each CT-stimulation. To assess sensory changes, quantitative-sensory-testing was performed at the beginning and the end of the trial period.CT-targeted-touch was felt more pleasant on the healthy compared to the affected limb on hairy (p < 0.001) and glabrous skin (p 0.002), independent of allodynia. In contrast to healthy controls patients felt no difference between stimulating glabrous and hairy skin on the affected limb. Thermal pain thresholds increased after CT-stimulation on the affected limb .CT-stimulation normalizes thermal pain thresholds but has no effect on the overall pain in CRPS. Therefore, pain modulating properties of CT-fibers might be too weak to alter chronic pain in CRPS. Moreover, CT-fibers appear to lose their ability to mediate pleasant aspects of touch in CRPS. Complex regional pain syndrome (CRPS) occurs in 2–5% of patients  sufferinQuantitative sensory testing in patients with CRPS expounded that sensory abnormalities are individually very different ranging from loss to gain of function for the same modality tested . Ott andThese findings point to a disinhibition of nociception in CRPS patients, whereas the large sensory fibers are intact .CT afferents are a subgroup of C fibers, the C-low threshold mechanoreceptive  afferents. Together with Aβ afferents, CT fibers mediate pleasant aspects of touch in human hairy skin. CT fibers were first detected in humans in the infraorbital nerve by microneurography  and haveIn addition, recent studies reported that CT stimulation can reduce experimental pain in healthy individuals . In pathThese observations gave rise to the question whether CT afferents have an impact on pain intensity as well as perception of allodynia or hyperalgesia in CRPS patients.10 patients with CRPS  as well as 11 healthy controls  were included in this pilot study.All participants gave their informed written consent according to the latest revision of the Declaration of Helsinki. The study was approved by the Rhineland–Palatinate Medical Association (registration number 4208).In all participants, a medical history was acquired, and a thorough neurological examination was undertaken. CRPS Type I and II were diagnosed according to the revised Budapest diagnostic criteria, scientific version . In brieFor healthy volunteers (n = 11) the medical history was uneventful in all participants and the clinical neurological examination was normal.We performed quantitative sensory testing on hairy skin of the affected and non-affected limb (dorsum of hand or foot) in every patient before and after performing CT stimulation, following the protocol of the German Research Network on Neuropathic Pain (DFNS) . The det2; ramp rate 1 °C/second). The threshold for cold and warm detection was calculated as mean of 4 consecutive measurements. Heat (HPT) and cold pain thresholds (CPT) were obtained by estimating the mean of 3 consecutive measurements. Thermal sensory limen (TSL) was assessed by alternating warm and cold stimuli (three times each), TSL was calculated as mean of the temperature differences. Participants were prompted to signal perceived temperature changes and were asked about paradoxical heat sensations (PHS). For mechanical pain thresholds (MPT) sets of calibrated pinpricks with a 0.25 mm flat-top cylindrical tip and a series of 7 forces (8–512 mN), geometrically spaced by a factor of 2  were used. Mechanical pain sensitivity (MPS) and dynamic mechanical allodynia (DMA) was assessed by pain rating (range 0–100) of 50 randomized stimuli in blocks of 10 stimuli, each block consisting of 7 pinprick and 3 tactile moving stimuli. MPS was calculated as mean of all pain ratings assessed during pinprick stimuli. Dynamic mechanical allodynia (DMA) was calculated as geometric mean of all numerical pain ratings by tactile moving stimuli.In brief, warm (WDT) and cold detection thresholds (CDT) were determined using a TSA 2001-II  following the standardized verbal instructions and protocol provided by the German Research Network on Neuropathic Pain (DNFS) .For the CRPS patients ADS  , PESa anSubjects with ADS scores higher or equal the value 23 were categorized as “with depressive symptoms”. MPSS 1–3 assesses levels of chronic pain . Von Korff Index distinguishes the degree of handicap (1 = low and 4 = high level of handicap). PDI is a questionnaire with 7 questions about impairment of daily life activities ranging from 0 (no impairment) to 10 .Repetitive stroking with a soft painter’s brush  was applied in proximal to distal direction on the hairy part of the affected limb and the contralateral side (CT targeted touch) as well as on glabrous skin . In healthy individuals stroking has been performed on the foot (dorsum and sole of the foot). To avoid inter-investigator variability stroking was always performed by the same investigator (SS).Tactile stimulation was performed over a period of 10 days, twice daily  in each patient. For visualization of the study sequence see Fig. The participants were asked to quantify their acute pain before (T0), during (T1), 30 min (T2), 60 min (T3) and 120 min (T4) after CT stimulation. To obtain comparable datasets pain intensity ratings at T0 (NRS(T0)) were set as 10, the proceeding ratings were estimated by multiplying with the quotient 10/NRS(T0). For better visualization of the results all parameters were divided by 10 afterwards.During CT stimulation, the participants were asked to rate the pleasantness of CT targeted touch. Pleasantness was rated with 4 numbers: 4: very pleasant, 3: pleasant, 2: slightly pleasant, 1: not pleasant to achieve reliable and distinct answers. Rating of “1” included the sensation of unpleasantness. This has been explained to all participants beforehand in detail. In addition, patients were asked to evaluate their pain intensity on a numeric rating scale with the anchors 0: no pain and 10: worst pain imaginable  software package. Kolmogorov–Smirnov tests of normality were run for all data sets to evaluate normal distribution. If normal distribution was confirmed (pain rating) parametric statistics like two-sample or one sample t-tests were performed as indicated in the experiment-specific results. If normal distribution could not be assumed (pleasantness rating) non-parametric tests like Mann–Whitney-U test was performed. All values are given as mean ± standard error of mean (SEM) and standard deviation (SD) or as median and interquartile range (IQR). Values were considered significant if p Differences of pain ratings at all points of investigation (T0 to T4) were analysed using a one-way ANOVA.single patient—Meancontrols)/SDcontrols [QST parameters were log transformed  and then transformed into z-scores (except PHS and DMA) using gender and age matched normative data published by  using thcontrols . Z-scorest vs 2nd QST). Supplementary a method demonstrated by Magerl and coworkers for statistical comparison of QST group data was utilized. This method compares mean QST z-scores of a patient group with an ideal virtual sample with a mean z-score of “0” and a standard deviation of “1” utilizing a two sided independent t-test [www.quantitativeskills.com/sisa/statistics/t-test).For statistical comparison of group data we performed paired t-tests for each QST parameter  and abnormal side-to-side differences of each QST parameter (difference of more than 2 SDs retrieved from the reference data group in z-scores between affected and control limb) according to Gierthmühlen and coworkers .ADS has been assessed in 9 patients . 5 patients rated a sum score ≥ 23 and were classified as “with depressive symptoms”.All other scores were assessed to characterize the participants, these scores did not enter the statistics, for details see Table st QST z-score = 9.56, SD 12.3; 2nd QST z-score = 6.92, SD 10.998). QST on the control limb showed no pathological parameters regarding the z-scores at group level. For details see Fig. The QST assessment on the affected limb revealed pathological z scores only for dynamic mechanical allodynia at both given points of testing . Hyperalgesia to heat pain showed the same trend .DMA on the affected limb was also significantly more pronounced than on the contralateral limb . All other parameters showed no difference between the test (affected limb) and control area (unaffected limb).The second QST revealed a significant difference comparing the investigation of the affected versus the unaffected limb regarding cold detection threshold . All other parameters displayed no difference between the test (affected limb) and control area (unaffected limb). Especially thermal pain thresholds and DMA aligned compared to the first QST.st CPT: mean 1.56, SD 0.78, SEM 0.26; 2nd CPT: mean 0.68, SD 1.53, SEM 0.51; p 0.016, paired t-test. 1st HPT: mean 1.41, SD 1.47, SEM 0.49; 2nd HPT: mean 0.52, SD 1.38, SEM 0.46; p 0.033, paired t-test). All QST parameter assessed on the control limb showed no significant difference over time. For Details see Fig. Thermal pain thresholds (CPT and HPT) aligned to thresholds, provided by healthy individuals, at the affected limb at 2nd QST . QST data of the control limb showed no significant difference compared to the ideal virtual sample. The second QST again showed significant abnormal thermal detection thresholds , whereas thermal pain thresholds and perception of allodynia aligned to normal values. TSL of the control limb was also significantly different to the ideal sample (p 0.021).st QST n = 10; 2nd QST n = 9, except for MPS, MPT and DMA, here one participant refused the investigation at 1st and 2nd QST). Analysis of MPS and MPT showed positive and negative signs. Absolute abnormal negative z-scores (negative signs) could be retrieved from all individuals for assessment of heat pain threshold (HPT). See also Fig. For most QST data absolute abnormal z-scores revealed “plus signs” on the affected limb in our patient group  loss and gain of function for CDT, WDT, TSL, MPS and MPT could be observed. Only gain of function could be observed for CPT, HPT, PHS and DMA. See also Fig. Kolmogorov–Smirnov test was significant (p < 0.001), therefore non-parametric tests have been performed.CT targeted touch was significantly more pleasant on hairy skin than on glabrous skin . For details see Fig. Pleasantness of CT targeted touch was not significantly different between hairy (CT fibers present) or glabrous skin on the affected limb . Stroking at the unaffected limb was significantly more pleasant on hairy skin  than on glabrous skin . CT targeted touch was significantly more pleasant on the contralateral limb than on the affected limb on hairy  and glabrous skin . See Fig. There were significant differences of pleasantness ratings comparing CRPS patients with and without depressive symptoms while CT stimulation on glabrous skin of both limbs . For details see Fig. CT targeted touch was less pleasant on the affected limb than on the contralateral limb regardless of stroking hairy or glabrous skin for patients with allodynia . See Fig. Patients suffering from allodynia rated CT targeted touch as less pleasant than patients without allodynia on the affected limb  but not on the contralateral limb. In patients with allodynia stroking the unaffected limb on hairy skin was more pleasant then stroking glabrous skin . For details see Fig. CRPS patients without allodynia showed significant lower pleasantness ratings of gentle stroking on the affected limb  but not on the contralateral limb. For details See Fig. Kolmogorov–Smirnov test was not significant and parametric tests have been performed.Pain ratings were highest during CT stimulation (T1). Only on day 2 and day 8 of the investigation, this effect reached level of significance . For further details see Figs. Patients with allodynia showed significantly higher pain intensities at T1 . There was no change of pain intensity over time. For further details, see Fig. There were no differences of pain intensity comparing patients with and without depressive symptoms . For further details, see Fig. Regarding the trend of pain intensity over time (day 1 till day 10), we observed significant lower pain intensities at T2 (30 min after CT stimulation) at day 10 compared to ratings at day 1 . This pain reduction could not be observed 1 and 2 h after CT stimulation  anymore. All the other points of pain ratings  showed no significant differences on the first and last day of the investigation. See Fig. Overall comparison of pain ratings at T0 to T4 showed a negative trend to lower pain ratings while the investigation (n.s.). See Fig. CT targeted touch is insufficient to reduce pain intensity in CRPS. This finding is independent from the presence of allodynia. In contrast, repetitive CT fiber stimulation increased thermal pain thresholds. Therefore, pain modulating capacities of CT fibers might exist even in chronic pain states but they are too weak to reduce intensity of chronic pain.CT stimulation by slow brush stroking did not reduce overall pain intensity in CRPS patients. Previous studies showed that intact CT fibers can modulate experimental pain , 31. HowFurthermore, thermal detection thresholds were reduced at the end of our trial, possibly pointing to a pathology of small diameter nerve fibers. Then again, the combination of hypalgesia to thermal pain and reduced thermal detection might be attributed to a refractoriness of e.g. TRP channels , 36. SinAll patients underwent also multimodal pain therapy, therefore it could be postulated that other therapies influenced our results. However, it appears obsolete that multimodal pain therapy would only act on experimental induced heat and cold pain. Auxiliary, Maher and coworkers investigated the effect of ketamine infusions and opioids on QST profiles and did not find significant effects on thermal pain thresholds . Other iTherefore we postulate that repetitive CT targeted touch reduced experimental induced pain in accordance to previous studies on healthy individuals .As expected, stroking on hairy skin was felt significantly more pleasant than on glabrous skin in healthy subjects. This can be reasoned by the histological distribution of CT fibers, which are known conductors of pleasant touch  and onlyIn CRPS patients, CT stimulation on the affected limb was less pleasant and there was no difference between stroking hairy or glabrous skin. Hence, CT fibers might lose their ability to mediate pleasant aspects of touch in chronic pain states. Some of our patients suffered from allodynia and, as expected, these patients felt stroking as less pleasant on the affected limb. However, our results cannot be simply explained by the presence of neuropathic pain since our CRPS patients without allodynia also rated CT touch as less pleasant on hairy skin of the affected limb than healthy controls. Furthermore, the observation that patients with allodynia rated pleasantness of CT touch as not different on glabrous or hairy skin of the affected limb, might indicate a more relevant loss of CT fiber function in patients with allodynia. On the other hand Nagi and coworkers demonstrated, that CT afferents in hairy skin mediated experimental vibration induced allodynia in healthy individuals . LiljencWhere does the pain modulating CT influence take place? Opioid blockade has been found to increase pleasantness of CT targeted touch in healthy individuals but not in chronic pain patients suffering from fibromyalgia , indicatCRPS patients are a heterogenous patient group especially regarding QST parameters . We inveSince all patients underwent multimodal pain therapy during the experiment, including drugs targeting the central nervous system, we cannot exclude effects of these therapies on our results. Effects of multimodal pain therapy on QST parameters have only been investigated for the long term .The relevant surveys found only mild changes (PPT and WUR reduced) , 50, whiDrugs against neuropathic pain  act systemic, but we only found changes of QST between both points of assessment at the affected leg, which makes a short term influence on QST parameters of these substances implausible.We did not perform skin biopsies to determine the intraepidermal nerve fiber density in both limbs, therefore we have no histological verification of the presence of small diameter nerve fibers, including CT afferents.Furthermore, it would have been interesting to investigate different stroking velocities to see, if e.g. Abeta fiber stimulation leads to different results. However, we only used CT fiber optimal stroking velocity to focus on the main goal of the study  and to avoid interference of other sensory stimuli with CT touch.CT-stimulation did not reduce pain intensity in CRPS patients and was less pleasant on the affected limb. Therefore, we present evidence that CT afferents lose their pain modulating properties in a chronic pain condition. It appears possible that CT-afferents might contribute to chronic pain in CRPS. Additionally, CT afferents seem to be involved in allodynia.


We examined relationships between various sociodemographic factors and attendance at the Glasgow Pain Management Programme (n = 2899 from 2011 to 2019). We tested for associations between gender, age and socioeconomic deprivation of patients who were invited to attend, and uptake to a programme when invited, attendance at screening assessment, eligibility, adherence and attendance at 3- and 6-month reviews. Uptake was significantly higher for patients from more affluent areas  = 0.93–0.99, p = 0.002) and for older patients , although effect sizes were very small. Patients were significantly more likely to be assessed as suitable if they were younger  or female . Attendance at sessions and at 3- and 6-month reviews was higher for patients from more affluent areas . We argue that there are multiple potential explanations for these findings and that future work should attempt to determine whether these patterns replicate in other populations and to determine any modifiable causes. Men are less likely to report chronic pain and, even when adjusting for this lower incidence, are less likely to seek treatment for pain than are women.2 Being socioeconomically disadvantaged is also associated with an increased incidence of chronic pain. Among those with pain, those who are socioeconomically deprived report the pain to be more severe and disabling. Reported severity of persistent pain following caesarean section, for example, was greater in Scottish women from areas of greater deprivation. Similarly, Clement et al. found deprivation to be positively correlated with the number of pain comorbidities and reported severity in Scottish patients undergoing knee replacement surgery for symptomatic osteoarthritis.A variety of sociodemographic factors have been shown to be associated with the risk of developing chronic pain. Greater age is associated with a higher prevalence of chronic pain. The reasons for these differences are undoubtedly complex and may or may not be open to modification. One factor that is open to change is ensuring that access to healthcare is fair and equitable across different sociodemographic groups. However, it has long been recognised that an ‘inverse care law’,810 which states that good medical care is least available to the populations that most need it, sometimes operates. In line with this is evidence of poorer provision of health services in deprived areas. For example, patients in more deprived areas in the West of Scotland reported slower access to care, lower satisfaction with access and shorter clinical encounters. In addition, deprivation may influence the likelihood of attending healthcare services and appointments. For example, patients with diabetes in Tayside, Scotland, were less likely to attend retinal screening if they came from an area of high deprivation and uptake of influenza immunisation was inversely correlated with deprivation across the United Kingdom.14These sociodemographic variables are associated with a number of other health-related factors, including access and response to treatment and, ultimately, to variations in mortality.Here we sought to identify key sociodemographic factors which influence uptake of invitation to attend, and attendance at, the Glasgow Pain Management Programme (GPMP). The catchment population for this programme includes some of Scotland’s most socially deprived areas. We collected data on the gender, age and socioeconomic deprivation of patients who were invited to attend the GPMP, and tested for associations between these with uptake of a programme when invited, attendance at screening assessment, eligibility, adherence and attendance at 3- and 6-month reviews.Appendix 1) are in line with those suggested by the British Pain Society.Our catchment area was the Greater Glasgow and Clyde NHS-Scotland Health Board. The board is the largest in the United Kingdom and provides healthcare to 1.14 million people. Patients are referred to the programme by the secondary care multidisciplinary pain team across three Glasgow hospitals. Inclusion criteria  to least deprived (ranked 6976). SIMD ranks are constructed from 30 ‘indicators of deprivation’, which reflect a variety of social, health and geographical issues at the local level. Each local level, or data zone in SIMD parlance, contains roughly the same number of people. Therefore, measurement is not taken at the individual or even household level; rather it reflects the daily realities of the 760 people, on average, who live in each data zone. These 30 indicators are then grouped into seven domains, which are weighted and combined to produce a total score which is then given a rank across the 6976 data zones that comprise Scotland. Here, we used SIMD-1617 deciles as our unit of analysis in inferential statistical tests.Using the Scottish Index of Multiple Deprivation ,The following were recorded: (1) uptake of invitation to screening assessment (yes or no), (2) attendance at screening assessment (yes or no), (3) eligibility (yes or no), (4) adherence (percentage of GPMP sessions attended), (5) attendance at 3-month review (yes or no) and (6) attendance at 6-month review (yes or no).17 deciles independently predicted the six outcome measures described above  generated skewness and kurtosis coefficients that were within parameters of normality for regression.For all analyses, continuous variables ; male n = 775 (26.8%); not reported n = 9; age: mean = 50, SD = 11.79). Non-responders were sent a further reminder. General Practitioners of non-responders were contacted individually, first to check that we had the correct patient address, and then to ask the General Practitioners to give patients a leaflet and further invitation to opt in to the GPMP.17 in the sample matched that of the population of the catchment area of Greater Glasgow and Clyde, as shown in 17 ranks of our sample (n = 2899) did not differ significantly from those of Greater Glasgow and Clyde .The distribution of SIMD-1617 deciles did not differ significantly between patients for whom age (t(1980) = –1.68, p = 0.093) or gender (t(1980) = –1.44, p = 0.15) were missing. Therefore, we included all patients in analyses.Of the 2899 patients who received an invitation, 1982 (68.4%) opted in to assessment for the programme and 917 (31.6%) did not. Of these, age was not available for 15 and gender was not available for nine patients. Independent samples t-tests revealed that SIMD-162 = 0.01), there was a very small, significant, relationship between SIMD-1617 decile and uptake of invitation to screening assessment (Exp(B) = 0.96 : 0.93–0.99), p = 0.002). 17 decile) regions. There was a very small, significant, relationship between age and uptake (Exp(B) = 0.99 (95% CI: 0.98–0.99), p = 0.006), such that those who responded were older than non-responders (see In binary logistic regression with age and gender as covariates (Nagelkerke Rders see . Gender 2 = 0.01) revealed no significant associations between gender (Exp (B) = 1.15, p = 0.712), age (Exp (B) = 1.01, p = 0.398) or SIMD-1617 decile (Exp (B) = 1.06, p = 0.297), and whether or not patients attended screening assessment.Of the 1982 patients who opted in for assessment, 1941 patients (97.93%) attended for screening assessment and 41 (2.1%) did not. Binary logistic regression with age and gender as covariates (Nagelkerke RAppendix 1 for details of assessment criteria) and 723 (37.2%) were not. Data on eligibility were missing for the remaining 55 (2.8%) of patients, so they were excluded from analysis.Of the 1941 patients who attended assessment, 1163 (59.9%) were classified by two members, from different professions, of the multidisciplinary team as suitable for the programme and offered a place (see 2 = 0.02) revealed a very small, significant, relationship between eligibility and age (Exp (B) = 0.99 (95% CI: 0.98–0.99), p = 0.013) and a medium, significant, relationship with gender (Exp (B) = 0.68 (95% CI: 0.55–0.84), p < 0.001). 17 decile did not significantly predict assessment of eligibility (Exp (B) = 0.99, p = 0.92).Binary logistic regression with age and gender as covariates (Nagelkerke R2 = 0.01) revealed no significant associations between gender (Exp (B) = 1.29, p = 0.113), age (Exp (B) = 0.99, p = 0.091) or SIMD-1617 decile (Exp (B) = 0.99, p = 0.752), and whether or not patients joined the programme.Of the 1163 eligible patients, 827 (71.1%) attended at least one session of a programme and 336 (28.9%) did not. Binary logistic regression with age and gender as covariates  = 2.47, p = 0.061) revealed no significant relationships between gender or age with adherence (both p > 0.1), but a small, significant, positive relationship between SIMD-1617 decile and adherence . That is, patients from areas with relatively lower deprivation attended more sessions.Of the 827 patients who joined a programme, data for adherence were missing for 252 (30.5%) patients. These were excluded from the analysis. Percentages of sessions attended were calculated for the remaining patients. Multiple linear regression with age and gender as covariates (Adj R2 = 0.03) showed that gender and age did not predict attendance at 3-month review (p > 0.2). SIMD-1617 decile predicted attendance (Exp (B) = 1.09, p < 0.001). Of the 827 who joined, 381 (46.1%) attended a 3-month review and 448 (53.9%) did not attend. Binary logistic regression with age and gender as covariates (Nagelkerke R2 = 0.01) showed that gender and age did not predict attendance at 6-month review (p > 0.06). SIMD-1617 decile predicted attendance (Exp (B) = 0.99, 95% CI: 1–1.1, p = 0.044). Two-hundred and eighty-five (34.5%) attended a 6-month review and 542 (65.5%) did not attend. Binary logistic regression with age and gender as covariates , which is consistent with well-established high-attrition rates at group interventions.19 Older patients were more likely to uptake an invitation to screening assessment, but less likely to be assessed as eligible, than were younger patients. Women were more likely than men to be assessed as eligible.We tested for relationships between age, gender and socioeconomic deprivation, with attendance at a pain management programme. We found that, in terms of the distribution of patients across SIMD-1617 deprivation profile of patients referred to the GPMP closely matched that of the population of Glasgow as a whole, it is perhaps premature to suggest that those from more deprived backgrounds are not discriminated against in terms of access to the GPMP. This hesitancy is due to the fact that rates of chronic pain are higher among those from more socioeconomically deprived areas and, therefore, it would be predicted that the proportion of the GPMP sample that came from the most deprived postcodes should be higher than the population base rate, which we did not find.While the SIMD-16 Then, when help is sought, gatekeepers, such as general practitioners and other primary care health workers, might be less likely to identify the problem among those from deprived areas, and when identified, they might be less likely to refer onto specialist pain services. There is some evidence that referral rates to secondary care for hip pain are lower among those from areas of higher deprivation so this might provide a partial explanation. This difference may well reflect a number of more general processes that have been observed in consultations in primary care, such as shorter consultation times and less ‘patient enablement’ among patients from poorer backgrounds when compared to their wealthier counterparts.There are a number of points on the journey between the onset of chronic pain and referral to the GPMP where factors could intervene to prevent referral. One possible explanation is that despite the higher prevalence of chronic pain, those in more deprived populations might be less likely to seek help from their general practitioner, although the limited evidence available does not suggest that this process is in operation among people with hip and knee pain. This review found that the related variables of education and social status did not predict drop-out, regardless of whether these variables were examined in univariate or multivariate analyses. Why our own findings differ from those produced by this review requires explanation.Our results demonstrated a relationship between socioeconomic deprivation uptake of an invitation to attend a pain management programme, and of attendance at sessions and at follow-up. These findings contrast with the results reported in a recent systematic review that looked at factors associated with drop-out from interdisciplinary pain management programmes.17 measure used here. One Scottish data linkage study with a very large sample investigated the factors that predicted the failure to attend multiple General Practice appointments. The authors reported that SIMD-1617 rank was one of the more potent predictors, out of list that also included age, sex and various practice factors. Similarly, an analysis conducted by NHS Health Scotland, of who fails to attend their first appointment following referral to secondary care, found that being in the most deprived SIMD-1617 decile more than doubled the risk of not attending. To understand why SIMD-1617 might predict attendance, when education and social status apparently do not, it is helpful to better understand the SIMD-1617 measure.The most obvious candidate in explaining this lack of agreement is the difference in measurement of socioeconomic disadvantage employed by the studies in that review  and the SIMD-1617 score. These statistics include the standardised mortality ratio, the percentage of the population in each postcode that is currently being prescribed medication for anxiety, depression and psychosis, standardised figures representing emergency stays in hospital as well as other population statistics that reflect rates of drug and alcohol-related admissions to hospital. Thus, the SIMD-1617 reflects the extra burden of disease in patients from more socioeconomically deprived areas. It is not difficult to imagine ways in which this extra burden could interfere with the ability to attend healthcare appointments. Indeed, another large Scottish data linkage study found that the number of long-term conditions a patient has was also a strong predictor of the risk of failing to attend general practice appointments. Geographical issues, such as the time taken to travel to local resources, including local general practitioner practices, also contribute to the total SIMD-1617 score and could reflect the difficulties in getting to appointments more generally.Locality health statistics contribute 14% to the total SIMD-1617 also reflects financial constraints, in that the levels of unemployment and the percentage of the locality that are in receipt of state benefits, both contribute to the weighted total score. It is not difficult to imagine that the financial costs of attendance at outpatient appointments are more relevant to those whose income is most limited. Similarly, there may be greater stress associated with juggling the demands of work and attendance at sessions, particularly for those with unstable or ‘zero hours’ employment. Regardless of the reasons for non-attendance in our sample, the results reported here add to the evidence suggesting that one way in which deprivation contributes to ill health is the difficulties it creates in accessing healthcare.The SIMD-162426 although the data reported here failed to find any association between GPMP attendance and age. However, the increased uptake in older patients might reflect similar processes. The fact that older patients were less likely to be assessed as suitable for a place on the programme may reflect processes related to age discrimination. Age discrimination in health care has been well documented and attitudes among some healthcare staff have been shown to be discriminatory. We are not suggesting that this is what has taken place here, although such attitudes can be unconscious. There are also a number of other possible reasons for this difference, not least of which is the greater burden of ill health and disability among older people. A significant component of this extra burden is the difficulties that are brought about by the treatment that these conditions require. These treatment burdens include multiple healthcare appointments, the use of multiple medications and the need to self-care. These burdens have been shown to affect treatment adherence, including attendance at medical appointments.29 It is also worth noting that the outcome from assessment is not simply a binary, yes or no decision. Instead, decisions are made as to the most appropriate service for the patient’s particular needs and circumstances, which often involves referral onto other services.Increasing age was associated with a greater uptake, but a reduced chance of being assessed as suitable. It is well documented that older age is associated with an increased likelihood of appointment attendanceTo summarise, we found relationships between socioeconomic deprivation and uptake of a pain management programme, and of attendance at sessions. We argue that there are multiple potential explanations for this, and that future work could try to examine the independent contributions of income, geographical constraints and the burden of associated ill health. We would also encourage work looking at interventions that might address this unequal access. Encouragingly, we did not find evidence to support an effect of patient socioeconomic deprivation on clinician assessment of suitability for the programme. This suggests that lower attendance rates among patients from areas of high deprivation are not due to discrimination in the availability of the service, but rather due to factors which are more likely to prevent attendance from those experiencing greater deprivation.Click here for additional data file.Supplemental material, Appendix for Sociodemographic predictors of attendance at a Scottish pain management programme by FR Moore, L Williams and M Dunbar in British Journal of Pain


The numeric rating scale (NRS) and the requirement of rescue analgesics were assessed. The requirement for rescue analgesics was significantly lower in the GWDR group than in the GWR group . At the post-anesthetic care unit (PACU), patients in the GWDR group had a lower NRS pain score (p < 0.001). In addition, in the postoperative 2nd hour, patients in the GWDR group had a significantly lower NRS than the GWR group . No remifentanil-related adverse effects were observed. We found that gradual withdrawal combined with drip infusion of remifentanil required less rescue analgesics and reduced pain scores. The new way of remifentanil administration may be effective to prevent RIH.Development of remifentanil-induced hyperalgesia (RIH) postoperatively is an unpleasant experience that requires further treatment. This study assessed the effects of gradual withdrawal combined with drip infusion of remifentanil on postoperative pain and the requirement for rescue analgesics. A total of 559 patients receiving total intravenous anesthesia with propofol and remifentanil were enrolled. All patients either underwent gradual withdrawal of remifentanil (GWR) or gradual withdrawal combined with drip infusion (GWDR) with a dose of 1 mcg·kg Opioids are a major component of analgesia in the clinical practice of anesthesia. Among them, the application of ultra-short-acting opioids, remifentanil, with its unique chemical structure and high lipid affinity, offers the potent and rapid-onset properties and plays a key role in total intravenous anesthesia (TIVA) . ConsequThe intraoperative use of short-acting opioids is associated with opioid-induced hyperalgesia (OIH) after surgery . Once eaStrategies aimed at mitigating remifentanil-induced hyperalgesia (RIH) have been reported, including the use of the lowest dosage of remifentanil, multimodal analgesia, and alternative management, such as another opioid and gradual withdrawal of remifentanil (GWR) .A randomized, double-blinded, placebo-controlled, crossover trial included 19 healthy volunteers and suggested that the GWR could reduce RIH in the heat pain test . In addiThis was a retrospective cohort study.This study was conducted at the Tri-Service General Hospital .After approval from the ethics committee (TSGHIRB No: 2-108-05-135) of Tri-Service General Hospital (TSGH), Taipei, Taiwan, relevant information was retrieved from the medical records and the electronic database of TSGH, and the requirement for written informed consent was waived by the IRB. This retrospective study included 559 American Society of Anesthesiologists (ASA) scores of I–III patients receiving surgery under TIVA with propofol and remifentanil from May 2018 to January 2019 without receiving postoperative patient-controlled analgesia. Three hundred and fifty-four patients were subjected to TIVA without remifentanil dripped (Group GWR) after extubation and 205 underwent surgery under the influence of drip infusion of remifentanil (Group GWDR) after extubation. No inhalation anesthesia, a combination of propofol and inhalation anesthesia, or regional anesthesia were used in these patients. The exclusion criteria were the use of inhalation anesthesia or propofol combined with inhalation anesthesia, regional anesthesia, pregnancy, previous substance abuse, a neuropsychiatric disorder, or age <20 years or >80 years.−1) in all patients. Tracheal intubation was facilitated with rocuronium 0.6–0.8 mg·kg−1. Anesthesia was maintained using concentration effect-site (Ce) of propofol with Schnider pharmacokinetic model ranged between 2.0–2.5 mcg·mL−1 and of remifentanil with Minto pharmacokinetic model ranged between 1.5–3.0 ng·mL−1 and a fresh gas flow of 0.3 L·min−1 of oxygen and air with inspired oxygen fraction 0.5. Repetitive bolus dosing of rocuronium (0.2 mg·kg−1) was administered as required during the return of neuromuscular function. The Ce of propofol and remifentanil was adjusted in the range of 0.2–0.5 mcg·mL−1 and 0.2–0.5 ng·mL−1, respectively, with necessary according to the hemodynamic changes and bispectral index (BIS) monitoring . End-tidal carbon dioxide pressure was maintained at 35–45 mmHg by modulating the ventilation rate and maximum airway pressure. Only patients undergoing thoracic surgery received an intraoperative intercostal nerve block. Thirty minutes before skin closure, ketorolac 30 mg was administered intravenously. At 10–20 min before the end of the surgery, patients were prescribed with the Ce of remifentanil tapering to 1 ng·mL−1. At the end of the surgery, propofol was discontinued while patients were ventilated with 100% oxygen at a fresh gas flow rate of 6 L·min−1 [No prior medications were prescribed before the induction of anesthesia. Standard hemodynamic monitoring, including non-invasive blood pressure, electrocardiography (lead II), pulse oximetry, and end-tidal carbon dioxide pressure, were performed. Anesthesia was induced by intravenous propofol and remifentanil via a TCI pump  and lidocaine  was assessed 30 min after extubation, and rescue analgesic, fentanyl 50 mcg, was administered if the patient’s pain was more than 3/10 of NRS or the patient requested due to intolerant pain. All patients were monitored under adequate surveillance, stayed at least 60 min in the PACU, and were discharged from the PACU toward the wards until NRS < 3/10 without nausea, vomiting, or any discomfort. In the ward, tramadol or NSAIDs were prescribed regularly for pain management and rescue analgesic with additional tramadol was prescribed if NRS ≥ 4 every 6 h. We also recorded NRS and adverse effects at 2 h after surgery.The retrospectively collected patient data were obtained from the medical records and electronic database: age at the time of surgery, demographic characteristics, body mass index (BMI), ASA score, NRS scores in the PACU, postoperative rescue analgesics, anesthesia time, surgical time, and perioperative consumption of propofol and remifentanil. To differentiate the effects of drip infusion of remifentanil on the degrees of pain, patients were classified into three pain categories by NRS scores, namely no pain (0), mild pain (1–3/10), and moderate to severe pain (≥4/10) which rescue analgesics were required . In addiBased on our institute data, a sample size analysis was performed with the incidence of rescue analgesics in PACU being 36 % after TIVA as the primary variable. To achieve a power of 90% at a two-tailed type I error of 0.05, at least 189 patients in each group were required to detect 40% (reduced from 36% to 21%) of the intergroup difference.The major aim of our study was to identify the effectiveness of drip infusion of remifentanil on postoperative pain. The primary outcome was the comparison of the requirement for postoperative rescue analgesics during PACU between the two groups. The secondary outcomes were NRS scores 30 min after extubation in the PACU and 2 h after surgery in the ward, the observation of adverse effects, the type of surgery, surgical site, and anesthetic consumption, which may influence the development of RIH.t-test or Mann-Whitney U test if the data were not distributed normally. Categorical variables were compared using the chi-square or Fisher’s exact test, when appropriate. Multinominal logistic regression analyses were used to evaluate the relationship between drip infusion of remifentanil and the degrees of pain (mild or moderate to severe pain vs. no pain), as well as rescue analgesics. In the multivariable models, variables were entered by forward selection to avoid multicollinearity. Estimates of odds ratios (ORs) and associated 95% confidence intervals (CIs) were obtained from these models. NRS was also treated as a continuous variable, and linear regression was used to assess the effect of postoperative drip infusion of remifentanil at the PACU as well as at the 2nd hour after surgery.Data are presented as mean ± standard deviation or number (percentage) of patients. Continuous variables were compared using the Student p-value of less than 0.05. Statistical analysis was performed using SPSS version 23 statistical software program .Statistical significance was accepted for a two-tailed p = 0.019). The surgical sites of the GWDR group were significantly more located on the skin and connective tissue, extremities, and chest than those of the GWR group (p < 0.001). The GWDR group had significantly more patients undergoing major surgery than the GWR group . The incidence of postoperative rescue analgesic requirement was lower in the GWDR group than in the GWR group . The GWDR group had a lower NRS score than GWR group (p < 0.001). There were only one and four patients in the GWR and GWDR groups, respectively, with NRS ≥ 7. There were too few patients with severe pain to be identified as the difference between the two groups. More propofol consumption was in the GWDR group than in the GWR group . No adverse effects, such as nausea, vomiting, hypotension, respiratory depression, requirement of oxygen or mechanical ventilation were found in the PACU and 2 h after surgery in both groups.A total of 559 patients who underwent surgery were reviewed, of which 205 received drip infusion of remifentanil and 354 received no intravenous medication after surgery. p < 0.001). Patients undergoing minor surgery had a significantly lower risk of suffering from mild pain than patients undergoing major surgery . Significantly more patients whose surgical sites were located on the musculoskeletal and abdominal regions experienced mild pain than those whose surgical site was located on the skin and connective tissue . Similarly, patients in the GWDR group had a significantly lower risk of experiencing moderate to severe pain (≥4/10) than the GWR group . Patients undergoing minor surgery had a significantly lower risk of suffering from moderate to severe pain than patients undergoing major surgery . Significantly more patients whose surgical sites were located in the musculoskeletal, chest, and abdominal regions had moderate to severe pain than those whose surgical site was located on the skin and connective tissue .p < 0.001), but also patients in the GWDR group had a significantly lower NRS in the postoperative 2nd hour than the GWR group . Patients who underwent minor surgery had significantly lower NRS scores than those who underwent major surgery at the PACU . In addition, multivariable analysis showed significantly higher NRS in the postoperative 2nd hour in the abdominal surgery (p = 0.016) and female sex (p < 0.001). In the postoperative 2nd hour, there was no significant difference in NRS in both patients undergoing major and minor surgery after univariate analysis .p < 0.001). Patients undergoing minor surgery had significantly fewer rescue analgesics than patients undergoing major surgery . Patients whose surgical sites were located in the musculoskeletal, chest, and abdominal regions required significantly more rescue analgesics than those whose surgical sites were located on the skin and connective tissue . Patients with higher body weight required fewer rescue analgesics than those with smaller body weight .Our retrospective study demonstrated that gradual withdrawal during surgery and drip infusion of remifentanil immediately after surgery effectively lowered the use of rescue analgesics as well as the NRS after 30 min at the PACU and the postoperative 2nd hour without respiratory depression. This result was consistent with previous reports ,9 with cd-aspartate receptors, and other transcriptional mechanisms [The development of OIH debates and the underlying cellular and molecular mechanisms are complex and involve interactions between neurons, glial cells, transient receptor potential vanilloid channels, cytokines, neurokinin-1 receptors, serotonin receptor type 3, cholecystokinin, μ opioid receptor signaling, long-term potentiation (LTP), N-methyl-chanisms ,11,12,132O) [−1) followed by an infusion (450 mcg·kg−1·hour−1 for 1 h) and tapered withdrawal of remifentanil for 30 min in vivo. They showed that withdrawal LTP may be prevented by tapering the remifentanil infusion instead of abrupt withdrawal through the mechanism of decrement of potentiation of spinal dorsal horn C-fiber-evoked field potentials in all five animals tested (p = 0.001). In brief, application of remifentanil in vivo leads to acute depression of synaptic strength in C-fibers; upon withdrawal, synaptic strength not only quickly returns to normal but becomes potentiated for prolonged periods of time [There are many strategies, such as propofol , ketamin2O) , non-ste2O) ,19, bupr2O) , etc., w2O)  investig of time . Consequ−1 for 30 min and gradual withdrawal by 0.6 ng·mL−1 every 5 min by TCI pump in healthy volunteers and concluded patients receiving GWR had significantly lower NRS scores without the development of RIH in heat pain but not cold test than those receiving the abrupt withdrawal. Saxena et al. [−1 2 h after thyroid surgery and revealed a significantly delayed demand for postoperative analgesics but an insignificant decrease in pain scores with gradual withdrawal of remifentanil. Lee et al. [−1·min−1 immediately after laparoscopic-assisted vaginal hysterectomy for 30 min with alfentanil-based patient-controlled analgesia showed a similar effect on pain scores and respiratory depression. The analgesic effects of GWR  in our study did not satisfy almost 36% of patients with requiring rescue analgesics. The result might be different from gradual withdrawal via 0.6 ng·mL−1 every 5 min for 15 min by Comelon et al. [−1) and the infusion period was short (30 min). In addition, the context sensitive half-time of remifentanil was 3.4 min.There are few studies on GWR in the prevention of RIH in clinical practice. Comelon et al.  describea et al.  illustrae et al.  reportedn et al. ,23,24,25−1·min−1) had significant higher visual analog pain scores and cumulative morphine consumption than those with administration lower dosage of remifentanil (0.1 ± 0.0 mcg·kg−1·min−1). Furthermore, administration of a cumulated dose greater than 50 mcg·kg−1 remifentanil intraoperatively would be associated with exacerbated postoperative pain score and/or multiplied opioid requisites [−1. We also showed that patients who had longer surgical and anesthesia times and higher consumption of propofol had a higher NRS and requirement of postoperative rescue analgesics than those who were not. Undoubtedly, our patients who underwent major surgery had higher pain scores and needed more rescue analgesics postoperatively than those who underwent minor surgery. Meanwhile, our patients undergoing thoracic surgery had no significant difference in mild pain (p = 0.083) and a marginally significant difference in moderate to severe pain (p = 0.048) in comparison of patients undergoing surgery of skin and connective tissue (A previous systemic review and meta-analysis enrolled 1494 patients in 27 studies and found a significant increase in acute pain at 4 and 24 h postoperatively after high intraoperative consumption of remifentanil and consequently higher morphine requirement on postoperative day 1 . Guignarquisites , but alle tissue , which mOur study had some limitations. First, this was a retrospective study. Patients were not randomly allocated, and characteristics, such as ASA score, type of surgery, and surgical sites, may have introduced uncontrolled biases. We could neither guarantee that all patients received drip infusion of remifentanil with the same protocol, even though we had checked all the anesthetic documents, including records of anesthetic, and consumption of remifentanil in the PACU for assurance of the properly practiced protocol. Moreover, this alternative modality has been practiced for several years . As a reWe first reported that patients receiving gradual withdrawal combined with drip infusion of remifentanil had significantly less rescue analgesics requirement without adverse effects and lower pain scores than those with only gradual withdrawal. This is a unique and a new method for the administration of remifentanil and may be an alternative strategy of gradual withdrawal that can efficiently decrease postoperative pain intensity and analgesic demand to prevent RIH.


Higher PA levels, displayed in higher self-efficacy reports , and return to prior job status (0.005). The PA level does not influence pain at one, three and 6 months postoperatively . High PA levels increase the risk of axillary web syndrome (p = 0.041), although, it reduces the incidence of chronic pain (p = 0.007). Women who practice physical activity recover better from BC surgery than sedentary women. The higher the intensity and frequency of training, the better the results. Vigorous activity cause axillary web syndrome, despite, it has a beneficial effect on lowering the rate of chronic pain.After breast cancer (BC) surgery, women may experience a physical decline. The effect of physical activity (PA) on the course of recovery after BC surgery has not yet been thoroughly examined. To analyze the impact of physical activity performed by women undergoing breast cancer surgery on measures of function, range of motion, and self-efficacy. A prospective study was carried out in 157 patients who underwent surgery for BC between October 2018 and April 2019, divided into four groups according to the intensity of PA with 6 months follow-up. 50 sedentary patients and 107 active patients were enrolled; the mean age was 52.6. Women who performed physical activity, moderate to vigorous, demonstrated lower function disabilities (QuickDASH 2.22) compared with inactivity or light physical activity (QuickDASH 7.0,  While research has traditionally focused on the association between cardio-respiratory fitness and health outcomes, the association between muscular fitness and health status has recently received increased attention2.Evidence for the health benefits of different sport disciplines was either inconclusive or tenuousThe effects of physical or sport activity, frequency, and intensity in the recovery process of patients that underwent breast cancer (BC) surgery have not been analysed in depth.6. Nonetheless, surgery remains today one of the pillars in the treatment of breast carcinoma that has implications for postoperative quality of life (QOL).In recent decades there was progress in prevention, diagnosis, and treatment of women with BC7. Additional impairments include reduction of grip-strength in 40% and restrictions of arm and shoulder movement in 35%, all of which have a negative impact on patients' QOL10. Physical activity (PA) has been found to be beneficial for women in improving postoperative function and reducing the restriction of movement11. Furthermore, exercise reduces the side effects of oncologic treatments including fatigue, depression, anxiety, sleep disturbances, and nausea associated with disease treatments12. Moreover, PA has been found to reduce the risk of recurrence of the disease, and a higher level of physical fitness was found to reduce the risk of mortality rates14.Pain is the most frequent impairment after BC treatment with a strong relationship to perceived disability reported by 60% of the patients15, reduces the length of hospitalization and sick leave after surgery16. While, women engaging in exercise preoperatively had greater shoulder flexion ROM at 1 month, which persisted over a year17. Furthermore, a higher preoperative level of PA is associated with a faster recovery three weeks post BC surgery18. Patients that did not exercise preoperatively are at higher risks for developing more severe pain at 1 and 3 months after surgery19. Moderate to vigorous PA may mitigate C-reactive protein levels that in the low inflammatory response is associated with morbidity and mortality in BC patients20. In contrast, vigorous exercise during the end of treatment can cause concerns specifically in regards to anemia, and weight loss21.Earlier studies examining the effect of regular exercise and the level of activity have been found to improves range of motion (ROM)The purpose of this study was to examine the effect of different levels of preoperative and postoperative PA on shoulder function, flexion and abduction ROM, and self-efficacy in women after BC surgery.A prospective trial was conducted in a single medical center in women that underwent BC surgery between October 2018 and April 2019. The trial was approved by the Helsinki Assuta Medical Center Review Board  and was registered on the National Institutes of Health's website . All patients provided written informed consent before enrollment. All methods were carried out in accordance with relevant guidelines and regulations.The study includes 188 women that underwent BC surgery. Inclusion criteria included women 18 years of age and older with functional independence, a diagnosis of BC, and planned surgical intervention. Exclusion criteria for participation were: Benign disease of the breast, cognitive disorders, fibromyalgia or chronic pain disorders, neurological disorders causing permanent disability, previous breast surgery, lymphedema before the surgery, previous shoulder surgery or injuries causing limited ROM, severe systemic diseases.22 and metabolic rate intensities (METs) that evaluate physical activities intensity23. Light PA (METs 1.1-3.0) included casual walking, stretching, Feldenkrais, Tai chi. Moderate PA (METs 3.0-6.0) included Pilates, Yoga, jogging, aerobics, bicycling, etc. Rigorous PA (METs > 6.0) included running, high-intensity fitness training, heavy lifting, swimming, and competitive sport such as basketball and football24.Subjects were evaluated using questionnaire for their activity levels and outcome measures before surgery and 1 month, 3 months, and 6 months after surgery. PA levels were recorded, using a self-reported adapted questionnaire, developed for the study. Participants were asked whether they exercise regularly, about the intensity of the activities , and how many hours on average are they training, 1–2 per week, 3–5 per week, more than 5 h per week. The questionnaire is partially based on the international PA questionnaire25 was used for assessing the physical function and upper limbs activity. ROM (abduction and flexion) were evaluated using DrGoniometer application26. Self-efficacy which represents how much the participant felt that she returned to preoperative function on a scale of 1 (unable to carry out activities by themselves) to 10 . Additional measures included the number of sick days and if returned to the same job status. Pain levels were measured in each follow-up, using the numeric pain rating scale (NPRS), in values ranging 0–1027. Number of sick days and if the patients returned to prior job status.The QuickDASH score was used. QuickDASH instrument was the main outcome measure used to evaluated shoulder functional disability. QuickDASH score28 after BC surgery (43.2 ± 18) was compared with the general population29 (10.1 ± 14.6) to estimate the sample size. Using this data and the probability of type I error was 0.05, and the probability of type II error was 0.2, 30 experimental subjects, and 30 control subjects were needed to reject the null hypothesis. Since 4 different groups were evaluated, with a probability of up to 20% dropping out of the study, 160 patients were planned to enter the study.To calculate sample size estimation the PS Power and Sample Size Calculations software p < 0.05.Statistical analysis was performed using the SPSS statistical package, Version 21 . The significance level was set at The non-parametric Mann–Whitney rank-sum test for independent samples was applied for testing the statistical significance of the difference between continuous parameters. Nominal variables were evaluated by the chi-squared test. A repeated measures approach (mixed ANOVA) was used for analyzing study groups as well as group by time interactions.A total of 157 patients were eligible for inclusion  sedentary and 107 subjects that routinely exercise. The level of PA was divided according to the MET into light 43 (27.4%), moderate 42 (26.8%), and vigorous 22 (14.0%).2. Most patients 77 (47.1%) had low stage cancer 1A, and the most common surgical procedure was a lumpectomy and sentinel lymph node biopsy 89 (56.7%), while 54 (34.4%) of patients had breast reconstruction procedures . Six months postoperative, mastectomy surgeries resulted in more functional limitation (QuickDASH 7.2 ± 11.1), pain (NPRS 1.1 ± 1.2) and decreased shoulder flexion (147.9° ± 22.5°) compared with lumpectomies , p = 0.022, p = 0.002 and p = 0.026 respectively.The mean patients' age was 52.2 and the mean BMI was 25.0 kg/mts 77 47.% had lowp = 0.016, p = 0.002 and p = 0.007 respectively.Axillar lymph node procedures resulted in more pain (NPRS 1.4 ± 1.1), functional decline (QuickDASH 9.5 ± 8.7) and decreased shoulder abduction (149.8° ± 19.3°) compared with sentinel lymph node biopsy  or no axillar involvement , p = 0.025, reported in Table p = 0.020. No significant differences were found regarding the influence of routine PA on function in the first month postoperative  compared to moderate PA (QuickDASH 7.2), light PA (QuickDASH 9.9), and inactive patients, (QuickDASH 11.0), p < 0.001. After 6 months, the differences between the groups narrowed and remained significant p = 0.007  compared with light (143.8°), moderate (152.1°), and vigorous activity (154.5°), at the significance level of 4.8° compp = 0.006. Similar differences were found after 6-months, p = 0.010.The shoulder flexion ROM improved in the same trend, so women who exercised preoperatively improved their ROM largely in the months after surgery compared with inactive patients. The moderate and vigorous activity levels had similar effect (152.2° and 151.2°), with the main differences being between the moderate activity (144.8°) and inactive patients (132.9°), at significance level of p = 0.278, p = 0.304, p = 0.304, respectively), reported in Table Pain was not found to be affected by the level of women's PA throughout the study at 1, 3, and 6 months postoperatively  relative to the light activity or inactivity (152.2° ± 19.4°), at significance level p = 0.008. Furthermore, the flexion ROM was higher of active patients (157° ± 17.9°) compared to low activity (150.7° ± 15.9°), significance level p = 0.007. In addition, self-efficacy was higher in active women at higher intensity and pain levels were lower, relative to women in the light or inactive group . Moreover, the more active women also returned to the same job status in higher percentages (p = 0.005).To examine separately the effect of training intensity on outcome measures, vigorous and moderate PA were compared with light PA or inactivity. Six months after surgery, women who performed moderate to high-intensity PA reported less functional limitation (QuickDASH 2.2 ± 4.2) compared to women who did not exercise or performed light PA (QuickDASH 7.0 ± 10.2) with a significance of p = 0.002), reported in Table The frequency of PA had a positive effect on patients' recovery. Six months postoperatively, sedentary women reported greater shoulder functional limitations, resulting in QuickDASH 8.5 ± 11.8. Training 1–2 h per week reported QuickDASH 4.4 ± 6.4; those who trained 3–5 h per week had QuickDASH of 2.1 ± 4.3. No functional limitations were reported by women who exercised more than 5 h per week resulting in QuickDASH 0 . Furthermore, self-efficacy was higher for women who had frequently trained (p < 0.001). Moreover, it was found that the higher the frequency of PA, the need for sick days decreased (p = 0.047) and the percentage of patients return to the preoperative job increased (p < 0.001). The frequency of activity did not affect pain values and number of sick days.Similarly, the higher the frequency of training, the higher the ROM of flexion and abduction (p = 0.006). Their abduction and flexion ROM were better 158.6° ± 14.1° and 155.4° ± 16.2° compared with inactive patients 149.5° ± 20.0° and 148.8° ± 20.5° (p = 0.007 and p = 0.044 respectively). Similar results were obtained for self-efficacy, active 10.4 ± 8.6 compared with inactive 8.6 ± 1.4 (p < 0.001) and even returned in higher percentages to the same work status (p < 0.001).Comparing between the women who were inactive and active throughout the study period (regardless of the type of activity), it was found that 6 months postoperatively, women in the PA group recovered better in measures of function QuickDASH 4.4 ± 2.9 compared with inactive patients QuickDASH 9.3 ± 12.5 (p = 0.041). On the other hand, the higher the intensity of training, the risk of chronic pain (lasting more than 3 months) decreases significantly (p = 0.007), reported in Table No effect on exercise intensity was found on the incidence of seroma, infections, and lymphedema. However, high PA levels increase the risk of axillary web syndrome p = 0.01. On the30. Following what was reported by Nilsson that a higher intensity of the preoperative PA level is associated with a faster self-reported physical recovery17, in this cohort preoperative PA improved functional disabilities, abduction and flexion ROM during the 6 months postoperatively, compared to sedentary women. In addition, the higher the intensity of the exercise, the better the recovery.Preoperative and pre-diagnosis sport activity had a major positive effect on the recovery process of oncologic BC surgery31 and improve health outcomes of BC survivors32. Additionally, among tamoxifen treated BC survivors, high PA levels before and after diagnosis were found to improve overall survival compared with inactive patients33.Sedentary patients needed more radiotherapy and neoadjuvant treatments, which may indicate that physically active patients have an earlier diagnosis of the disease or a less aggressive presentation, which is an important point for future research. Physical activity can reduce cancer recurrence, mortality36. The results from this study are a continuation of previous publications and attempt to give a broader picture of the effect of exercise on the course of recovery. Six months postoperatively, a return to exercise contributed to an improvement in function limitations and ROM. Unlike previous findings11, it was not found that PA had an effect on pain reduction. This finding can be explained because, during hospitalization, patients were instructed to report any type of pain and the to receive apropiate treatment37. Furthermore, the patients received instructions on how to cote with pain during daily activities and physical affair. Both can contribute to pain reduction, due to the emphasis in pain management.Postoperative exercises for BC patients are effective in reducing pain and improving ROM38. In our results, women who were sedentary before surgery and started PA postoperatively did not improve their function, ROM and pain levels, or self-efficacy significantly, compared to sedentary women, although this may be attributed to the small sample of patients given for comparison, further studies may be necessary to corroborate this issue.Pickett et al. reported that women who exercised regularly before receiving a BC diagnosis, attempted to maintain their exercise programs, and therefore BC survivors who lead sedentary lifestyles are the ones that may benefit more from a structured exercise program40. Our results are consistent, finding that the higher the intensity of training, the greater the effect on recovery from surgery.The effect of high intensity PA evaluated during chemotherapy, showed that vigorous training was more beneficial than moderate or low PA in preventing side effects of treatment in terms of QOL, strength, fatigue, body weight and return to routine activities41. Our results demonstrated that the longer duration of PA was associated with fewer functional limitations, higher self-efficacy, better flexion, and abduction ROM, and the need for less sick days.Another aspect is the effect of the duration of PA rather than intensity, as previous study found that higher duration of PA was associated with better improvement in shoulder ROM42.Moreover, regular PA helped patients to return to previous job status compared with inactive women. Lee et al. have reported similar results, finding patients who exercise before, during, and after treatment for BC are more likely to return to prior work43. New studies have examined the effect of intense training including weight lifting after breast surgery and have found no direct link to the development or exacerbation of lymphedema45.The results of the study did not show associations between the level of PA and the degree of acute postoperative short-term complications such as seroma, bleeding, infections and nor the long-term complication of lymphedema. Until recently, intense PA has been associated with the development of lymphedema after BC46. In this study, we found an association between vigorous PA performance and risk of developing AWS. The authors who previously examined risk factors for developing AWS found no relationship between training level and increased risk of AWS48, with the exception of a case report that described AWS development after physical effort49. Moreover, among the risk factors for the development of AWS should be considered younger age, greater time elapsed since surgery and number of resected lymph nodes50, but PA was not considered.Axillar web syndrome (AWS) is a self-limiting complication of axillar surgery51. A positive association was found between the level of intensity of the PA and of chronic pain, the higher the activity levels the lower the incidence of chronic pain, and the severity of the pain. These results are a continuation of the results of Forsythe et al. who reported that weight gain and lack of PA place BC survivors at risk for pain long after treatment ends52. In addition, Galiano-Castillo et al. found that performing tailored online training for 8 weeks improved pain severity, compared with control53.Chronic pain in BC surgery appears after 3 months, the risk factors being extension of the surgery, intensity of acute pain and radiotherapyThe limitations of the study are based on the complexity and possible variations of the pre- and post-operative treatments. Long-term follow-up is necessary to verify the effect of sport on chronic disabilities.The strength of the study was in a broad examination of the effect of exercise before and after surgery on the course of recovery that allows us to affirm that sport is beneficial in the postoperative recovery and can be practiced without fear of causing complications. Furthermore, the separation into groups of patients according to intensity and frequency of PA provides relevant data from the present study.Physical activity improves recovery in patients who underwent surgery for breast cancer. Physical activity resulted in improved function, range of motion, self-efficacy, pain, with higher return to prior work. The higher the intensity and frequency of training, the greater the was the improvement. Vigorous exercise may cause more cases of axillar web syndrome, however also reduce the incidence of prolonged postoperative pain.Supplementary Table 1.Supplementary Table 2.Supplementary Table 3.Supplementary Table 4.


Low back pain (LBP) is among the top three most common diseases worldwide, resulting in a life with pain-related disability. To date, no study has assessed the efficacy of metamizole (dipyrone), a non-opioid analgesic and antipyretic prodrug compared with the conventional non-steroidal anti-inflammatory drug ibuprofen, in patients with an acute LBP episode. Further, it is unclear, whether a short educational intervention is superior to usual care alone.The objective of this study is to assess first, whether metamizole is non-inferior to ibuprofen in a new episode of acute or subacute LBP. Second, we aim to assess whether a short educational intervention including evidence-based patient information on the nature of LBP is superior to usual care alone.An investigator-initiated multicentre, randomised, double blind trial using a factorial design will be performed. A total of 120 participants with a new episode of LBP will be recruited from GP practices, outpatient clinics and from emergency departments, and randomised into four different treatment groups: ibuprofen alone, ibuprofen and short intervention, metamizole alone, metamizole and short intervention. The primary endpoint for the medical treatment will be change in pain assessed on an 11-point Numeric Rating Scale after 14 days. The primary outcome for the short intervention will be change in the Core Outcome Measures Index assessed after 42 days.This study has been approved by the responsible Ethics Board (Ethikkommission Bern/2018-01986) and the Swiss Agency for Therapeutic Products (Swissmedic/2019DR4002). Results will be published in open access policy peer-reviewed journals. The study is funded by the Swiss National Science Foundation (grant number 32 003B-179346).NCT04111315 This is the first randomised double-blind study assessing the analgesic effect of metamizole compared with the conventional non-steroidal anti-inflammatory drug ibuprofen in patients with acute or subacute low back pain (LBP) presenting to the GP or emergency department.In addition, this study will assess whether a short educational intervention is more effective in patients with LBP compared with usual care.Due to the high proportion of patients who will not require extended pain treatment during an acute LBP episode, the trial design mirrors current clinical practice.The primary endpoint pain intensity will be assessed after 14 days. The primary outcome for the short intervention will be assessed after 42 days.While patients, physicians and researchers are blinded to the pharmacological treatment, blinding is not feasible for the short educational intervention.Low back pain (LBP) is among the top three most common diseases worldwide, resulting in a life with pain-related disability.Current treatment guidelines recommend non-steroidal anti-inflammatory drugs (NSAIDs) for acute pain control.30Many patients have reservations against regular intake of pain medication and, contrary to guideline recommendations, limit physical activity to keep pain manageable without medication.The first objective of this study is to assess whether metamizole is non-inferior to ibuprofen in patients with a new episode of acute or subacute LBP. The second objective is to assess whether a short educational intervention, including evidence-based patient information on the nature of LBP, is superior to usual care alone. Thus, this randomised trial will provide new knowledge regarding the efficacy of non-opioid pain medications in LBP. In addition, if the short educational intervention proves to be beneficial compared with usual care, the trial will help to improve care for patients with a new LBP episode.The methods reporting of this randomised trial will follow the recommendations of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement.33The Efficacy of Metamizole versus Ibuprofen and a Short Educational Intervention versus Standard Care in Acute and Subacute Low Back Pain (EMISI) study is a multicentre, randomised, double-blind trial using a factorial design to investigate whether metamizole is non-inferior to ibuprofen in patients with a new-onset LBP episode. Patients, physicians and researchers will be blinded to the allocation of the study medication. A non-inferiority design was chosen as metamizole seems to be equally effective as ibuprofen in clinical practice. Furthermore, the study will assess whether a short educational intervention including evidence-based patient information is superior to usual care. Blinding patients about the short intervention is not possible but blinding is upheld in GPs and researchers (double blind). The primary evaluation of outcomes (see the Outcome measure section for details) will be performed at day 14 (comparison of metamizole to ibuprofen) and at day 42 .Subjects fulfilling all of the following inclusion criteria are eligible for the study:Age 18 years or older.Seeking care for new onset of non-specific or specific LBP (pain duration of less than 12 weeks LBP prior to the baseline visit).The GP plans to prescribe a non-opioid pain medication for pain control.Informed consent documented by signature.Exclusion criteria are:Chronic use of opioids.Presence of red flags .Known intolerance to the study medication .Active malignancy and/or history of a (previous) haematological disorder (history of agranulocytosis).9/L), thrombocytopaenia (<100 G/L).History of anaemia (haemoglobin of <10.0 g/L), neutropaenia (leucocyte count of <3.0 x 102) or previous acute kidney injury  definition).Known contraindications against the study medications: previous gastrointestinal ulcer/bleeding, inflammatory bowel disease, heart failure (New York Heart Association (NYHA) Functional Classification III–IV), liver failure , renal insufficiency (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 mImmune deficiency or under immunosuppressant treatment.Known or suspected non-compliance, drug or alcohol abuse.Participation in another study within 30 days preceding randomisation and during the present study or previous enrolment into the current study.Enrolment of the investigator, his/her family members, employees and other dependent persons.Pregnancy: In women of childbearing age, a negative pregnancy test (urine or blood test as available in the primary care practice) before inclusion is required. Women who are not willing to use safe contraception (condom or birth control pill) during the trial, intention to become pregnant during the trial, pregnancy or breast feeding.The EMISI trial will be coordinated by the central study team at the Division of General Internal Medicine, University Hospital Bern, Switzerland. Patients will be recruited from outpatient clinics, from GP practices, and from emergency departments. The overall study duration of 42 days (6 weeks) was chosen because treatment guidelines recommend further assessment of patients for multidisciplinary treatment if LBP persists for more than 6 weeks despite pain medication and the advice to stay active. This is an investigator-initiated trial. The funder will have no role in the study design, the trial oversight, data collection, analysis of the study and publication of the results.Both interventions are considered for determining the sample size for this factorial trial.The sample size calculation for the comparison of metamizole versus ibuprofen was based on a difference in the change of pain score in the Numeric Rating Scale . We considered a change of ≥2 points between the two groups as clinically relevant and a change of ≤1 point as negligible.et alThe sample size for the primary outcome comparison short intervention versus usual care (superiority) is based on a change in Core Outcome Measures Index  from baseline to week 6. We hypothesise that there is a difference between the two intervention groups regarding COMI. Mannion 38The primary outcome for the comparison of the short intervention versus usual care is the change in the COMI sum-score (range 0–10) from baseline to 42 days follow-up (superiority). The COMI is a short, multidimensional, validated outcome instrument with excellent psychometric properties recommended for the monitoring of the outcome in patients undergoing treatment for LBP.Pain domain: higher of the two pain scores (higher of 2a and 2b) is taken as the score.Disability domain: the average of the two disability items (6 and 7).Back related function (item 3).Symptom specific well-being (item 4).General quality of life (item 5).The five domain scores are then averaged to give a COMI score from 0 to 10.Two additional questions cover the satisfaction with treatment outcome. An MCID found to be relevant for patients was a reduction in COMI score of ≥2.2 points.37All outcome measures used in this study were recommended by the NIH Task force and other expert panels to study back pain.33Secondary outcome measures include:Change in pain on the NRS (range 0–10 points) from baseline to follow-up at day 42.Change in the COMI sum-score (range 0–10) from baseline to 14 days follow-up.The proportion of patients with an MCID in the NRS (≥2 points) and COMI (≥2.2 points) at days 14 and 42.Time to recovery (recovery defined as the first day with an NRS of <2 points sustained for two consecutive days).Change in overall pain intensity from baseline to follow-up at day 14 and day 42. Overall pain intensity: average of ratings for average pain, pain at rest, and pain during activity during the last 24 hours.Area under effect curve (day 0–14) NRS.AEs.Time to stopping treatment.Global effectiveness of the treatment .Daily physical activity (daily step count).Use of pain medication and additional rescue medication.Additional treatment .Return to work (yes/no).Treatment satisfaction (COMI).Quality of life as assessed by the 5-level version of the European Quality of Life-5 Dimensions questionnaire (EQ-5D).Psychological factors (STarT-Back Tool).43Response to pain medications may be influenced by individual pharmacokinetic and pharmacodynamics factors. Therefore, we will collect blood samples during visit 2 (day 14) to assess the following factors that may influence the individual response to the pain medications. First, we will measure plasma concentrations of ibuprofen and the four main metamizole metabolites . Pharmacodynamic effects of metamizole correlate primarily with concentrations of the 4-MAA metabolite,45Second, as individual response to ibuprofen may be affected by genetic polymorphisms of cytochrome P450 (CYP) isoforms 2C8 and 2C9, the study population will be characterised in terms of CYP 2C8/9 genotypes . In subjects with alleles conferring low CYP2C8 and/or CYP2C9 activity, reduced ibuprofen clearance of both enantiomers has been described, resulting in several-fold increased exposure and prolonged half-life compared with subjects with wild-type alleles.46 47Study procedures are summarised in the study flow chart . Each paPatients will complete a set of self-reported questionnaires see . PhysiciOn completion of the baseline evaluation, patients may open the intervention pack and start treatment. The intervention pack will contain a pill bottle and an envelope with the assignment of the short versus no intervention and a pain diary.Between the first and the second visit, patients will record their pain before intake of study drug, the number of study drugs and additional pain medications, and their daily physical activity .2), leucopaenia (leucocyte count <3.0 G/L), thrombocytopaenia (defined as <100 G/L) and/or anaemia ((haemoglobin <100 g/L), we will stop the study medication.To mitigate the risk for AEs, we will collect blood samples after the randomisation in all patients. In case of a newly detected renal insufficiency (defined as eGFR <60 mL/min/1.73 mDuring the second visit (day 14), patients will return the pill bottles and the pain diary to the GPs office where they are collected for pill count. The patient will receive a new drug pack and pain diary. A blood sample will be collected , and self-reported questionnaires and a clinical assessment will be completed. The GP will record the clinical findings and additional pharmacological and non-pharmacological treatments.To improve adherence, study staff will call patients between the first and the second visit and between the second and the final visit and ask for AEs and additional pain treatment. As we expect a high proportion of patients to have recovered by day 28 , researchers will then determine whether a clinical visit on day 42 is necessary. In case patients have recovered by day 28, patients do not need to attend the clinical visit. Patients will be asked whether they would be willing to participate in an in-person interview at the end of the study. The aim of the interview is to assess factors that were relevant for patients during their LBP treatment. The interview will be recorded (video and audio) for qualitative analysis using standard grounded theory method according to Philipp Mayring.50A final assessment will be done on day 42 during a clinical visit in patients who had persisting symptoms on day 28. Patients will return the pain diary and the pill bottles with the remaining pills to the GPs office where they are collected for pill count. Data collection includes self-reported validated questionnaires. The GP will record the clinical findings and additional pharmacological and non-pharmacological treatments. A final blood sample (serum creatinine and blood count) will only be collected if patients are still taking study medication. Patients who do not need to attend the clinical visit will receive a final identical set of questionnaires by mail and will be asked for AE/SAE and additional treatments during a phone call. Patients will return the questionnaires together with the pain diary and the pill bottles to the central study team. To assess the success of blinding, patients will be asked at the end of the study what treatment group they believe they had been assigned to (metamizole or ibuprofen).During the first 4 days, we will compare a fixed-dose regimen of metamizole 500mg to 500 mg ibuprofen lysine (lysine-2-(4-isobutylphenyl)-propionate, corresponds to 292.6 mg ibuprofen acid) three times two capsules per day . Ibuprof52In LBP, current clinical practice is to prescribe an initial fixed dose regimen followed by an as-needed regimen that allows patients to adjust the daily dose depending on their pain intensity. To mirror clinical practice, patients will be allowed after the first 4 days to decrease the intake of the study medication according to a dose reduction schedule (as needed phase). From day 4 until recovery, patients may reduce the daily pain medication intake once their pain has decreased to less than four points on the NRS (range 0–10 points) every 2 days. The treatment duration will thus depend on the duration of pain. Patients are considered to have recovered when their pain is below 2 (NRS 0–10) on two consecutive days after they have stopped intake of pain medication (end of treatment).The Back Book.Patients assigned to the short intervention will receive together with the pain medication a short leaflet focusing on the nature of non-specific LBP and the importance of staying active. A second leaflet contains exercises to alleviate LBP. The content of the short information leaflet is based on the In a double-blind randomized clinical trial (RCT) comparing paracetamol to placebo for LBP in the primary care setting, rescue medications were infrequently used.The allocation sequence (randomisation list) will be generated by an independent data manager at the clinical trial unit (CTU) Bern who is not otherwise involved in the trial. Randomisation will be blocked and stratified according to study sites. To ensure concealment of allocation, block size will not be communicated. After patient data are registered in the CDMS, eligibility is confirmed and signed informed consent is obtained, patients will be assigned to the next sequentially coded intervention pack that is available at the recruiting site. Patients are randomised 1:1:1:1 into one of four groups: Metamizole +educational intervention versus metamizole +standard care versus ibuprofen +educational intervention versus ibuprofen +standard care. The intervention packs will contain a pill bottle and an envelope with the assignment of the short versus no intervention. The intervention packs will be prepared according to the randomisation list by an independent hospital pharmacist not involved in the study.Staff at the hospital pharmacy not involved in patient recruitment or other trial activities will fill the gelatin capsules with the study medication and label the pill bottles according to a standard operating procedure and based on the randomisation list provided by the CTU Bern. The study medication will be delivered in identically labelled sealed pill bottles containing capsules of identical appearance. The randomisation list will be kept electronically at the CTU Bern in a password-protected file. Study personnel and physicians involved in patient recruitment, treatment and outcome assessment will have no access to the list.Due to the nature of the short educational intervention, no blinding of patients receiving an information leaflet and a telephone call is possible. Therefore, contamination and performance bias are important to consider. The envelope including the leaflet will be sealed and the patients will be instructed to open de envelope outside the GPs office. GPs will not be informed about the group assignment and the content and aim of the educational intervention. Patients assigned to the educational intervention will receive a telephone call according to a predefined script by a member of the study team otherwise not involved in patient recruitment, outcome assessment and data analysis. To minimise the risk of detection bias, the study outcomes are collected in pain diaries and self-reported questionnaires . Study personnel that will contact patients by phone for reminders and to collect information on AEs will be blinded to the group assignment. To assess differences in additional treatments (performance bias), patients and GPs will record additional treatments other than the study medication and the educational information .The statistician responsible for the final analysis will also have no access to the list until the primary analysis of the trial is finished. Data analysis will be done according to a prespecified analysis plan before the randomisation code will be broken. Patients, physicians and data analysts will be blinded with regard to the allocation to the study medication until after the primary analysis. To assess the success of blinding, we will ask patients at the end of the study into which group they belief they had been assigned to. Data on all recruited patients will be collected and regularly monitored.The statistical analysis will be performed in compliance with the International Conference on Harmonisation’s Good Clinical Practice guidelines and the report will be developed in line with the Consolidated Standards of Reporting Trials statement.To assess the efficacy for the two primary outcomes, we will use two analysis sets see . The fulWe will present patient and procedural characteristics using descriptive statistics .To compare the efficacy of metamizole and ibuprofen (non-inferiority), we use an ITT (FAS set) and a PP analysis (PP set) for the primary outcome (NRS change from baseline to follow-up at 14 days). Both analyses need to meet non-inferiority in order to claim success. The difference in the change in NRS between the two groups will be calculated from a linear model, adjusted for the baseline NRS value and the type of intervention (short intervention vs standard care). If the lower one-sided 97.5% confidence limit of the difference lies above the non-inferiority margin of −1, non-inferiority will be claimed. If we can demonstrate non-inferiority, we will additionally test for superiority at a two-sided significance level of 2.5%. Since testing is nested , this procedure has no implication on the overall type-I error rate.To compare the primary outcome between the short educational intervention to usual care (superiority), we use ITT analysis (COMI change from baseline to day 42). The difference in the change in COMI between the two groups will be calculated and tested at a two-sided significance level of 2.5% using a linear model, adjusted for the baseline COMI and the type of drug treatment. Differences will be presented with a two-sided 97.5% CI and the regular 95% CI.We will assess both primary outcomes for interaction. We will introduce an interaction term between the treatment indicator and the intervention indicator to test whether in (A) the effect of the metamizole treatment on the change in NRS at day 14 is different in patients that receive the short intervention compared with the standard care group and in (B) whether the effect of the short intervention on the change in COMI at day 42 is different in patients that receive metamizole compared with patients that receive ibuprofen.Secondary continuous outcomes will be analysed as the primary outcomes. Besides the indicator for the drug treatment or intervention, models will be adjusted for the baseline value if available. Secondary binary outcomes will be analysed using logistic regression models adjusted for the indicator for the drug treatment or intervention, as applicable. Time-to-event outcomes will be analysed using Cox regression adjusted for the indicator for the drug treatment or intervention, as applicable. For all secondary effect measures, we will display regular two-sided 95% CI and accompanying p values.Further, we will perform additional PP analyses for the primary outcome of the comparison between the two intervention arms as well as for all secondary outcomes. If outcomes are missing, we will employ multiple imputation in the primary analysis and additionally perform an available case analysis disregarding missing data. Continuous outcomes that are measured several times during follow-up will additionally be evaluated in a repeated measures mixed-effects linear model, additionally introducing a random intercept for patients into the model.Exploratory analysis will be conducted with regards to predictors for treatment responses. We will explore the association between clinical predictors , drug levels, or genetic mutations and the treatment response in linear models. We will perform subgroup analyses according to gender, genetic phenotypes and drug levels.Safety outcomes will be reported as proportion and 95% CI separately for the two drug treatment groups using the safety population  set.Patients with missing outcome data will be imputed using multiple imputation.Protocol violations should not lead to treatment discontinuation unless they indicate a significant risk to patient safety.Patients may be withdrawn from the study treatment for the following reasons:Haematological disorders including leucopaenia  and anaemia (decrease in haemoglobin ≥20 g/L or <100 g/L).Potential evidence for a haematological disease .2) or AKI stage 1 or higher .Decreased kidney function . The investigators will report any serious AEs occurring during clinical trials, independent of direct causal relationship with the treatment, within 24 hours. In case of a suspected unexpected serious adverse reaction, Swissmedic will be notified by the sponsor–investigator within the legal timelines. Unblinding will be permissible in case the information is required to ensure the patients safety in case of an AE.All AEs are reviewed by a safety committee and graded according to the National Health Service (NIH) Common Terminology Criteria for Adverse Events (CTCAE V.5.0).54In this study, we use information material developed by patient advocacy groups. The results of this study will be communicated to the patients and physicians participating in the trial. The results will also be communicated to patients’ advocacy groups and may help to improve the information material. Further, we will assess the impact of the study on patients and factors that may be facilitators or barriers to improve pain and pain management in LBP during in-person interviews.During an LBP episode treatment guideline recommend to alleviate pain using pain medication and to stay physically active. To alleviate pain, NSAIDs are frequently used. However, the use of NSAIDs may be limited because of common adverse effects. Metamizole has a favourable adverse effects profile and may be used as an alternative. However, there is a lack of data on its effectiveness and safety for the treatment of LBP. This is the first study that systematically investigates the efficacy of metamizole in LBP patients undergoing treatment over the course of several weeks. Therefore, this study will provide evidence to support or discourage the use of metamizole in LBP. The findings of this study will be especially relevant for those patients where NSAIDs should not be used. Moreover, this trial is expected to provide evidence for a highly needed non-opioid treatment alternative in musculoskeletal pain. In particular, because the use of opioids has been shown to be no more effective than non-opioid medicationNon-pharmacological educational measures may potentiate the effect of the pain medication in acute LBP by addressing misbeliefs and avoiding disuse. Despite good evidence that staying active during an acute LBP episode is more effective than bed rest,The trial will be performed in compliance with the Declaration of Helsinki and its amendments, and has been approved by the responsible Ethics Board (Ethikkommission Bern/2018-01986) and the Swiss Agency for Therapeutic Products (Swissmedic/2019DR4002). Important protocol modifications will be communicated to the Ethics Board and participating study sites. Potential participants must provide written informed consent before entering the study. Subjects can leave the study at any time for any reason without any negative consequences for their further treatment. When a patient ends the treatment phase of the study prematurely, we will record the date and reason for early treatment discontinuation. If possible, the end of treatment evaluations will be collected before the patient is started on any other therapeutic intervention. Insurance coverage will be provided for all study participants by the study sponsor.The results of the main trial and each of the secondary outcomes will be submitted for publication in open access peer-reviewed journals. Results will be disseminated to all participating centres and participants expressing interest. The EMISI study group is an independent academic research group, which will not employ professional writers. The EMISI study group will comply with the open access regulation of the Swiss National Science Foundation.