The cause of pain in a phantom limb after partial or complete deafferentation is an important problem. A popular but increasingly controversial theory is that it results from maladaptive reorganization of the sensorimotor cortex, suggesting that experimental induction of further reorganization should affect the pain, especially if it results in functional restoration. Here we use a brain–machine interface (BMI) based on real-time magnetoencephalography signals to reconstruct affected hand movements with a robotic hand. BMI training induces significant plasticity in the sensorimotor cortex, manifested as improved discriminability of movement information and enhanced prosthetic control. Contrary to our expectation that functional restoration would reduce pain, the BMI training with the phantom hand intensifies the pain. In contrast, BMI training designed to dissociate the prosthetic and phantom hands actually reduces pain. These results reveal a functional relevance between sensorimotor cortical plasticity and pain, and may provide a novel treatment with BMI neurofeedback. Pain in a phantom limb after limb deafferentation may be due to maladaptive sensorimotor representation. Here the authors find that sensorimotor plasticity induced by BMI training with the phantom hand, contrary to expectation, increased pain while dissociating prosthetic movements from the phantom arm relieved the pain. Phantom limb pain describes the intractable chronic pain3467591011However, recent evidence has caused researchers to question the maladaptive sensorimotor reorganization model, especially in terms of the motor representation of the phantom limb. For example, it has been shown that when using ‘unfolded' brain maps to study anatomical reorganization of the phantom hand, shifts in the peaks of lip representations are local, do not invade the hand area and are not correlated with painRecently, it has been shown that brain–machine interfaces (BMIs) can not only reconstruct motor function in severely paralysed patients1718202224Here we apply the BMI training of a neuroprosthetic (robotic) hand using real-time MEG signals in phantom limb patients, whose symptoms are primarily caused by nerve avulsion, and evaluate the association between changes in their symptomatic pain and in cortical currents during phantom hand movements. We show that the patients partially restore the function of the affected hand by using the prosthetic hand in its place. According to the principle of restoration of function, it is initially hypothesized that successful BMI training using decoded phantom hand movements should reduce pain with concurrent plastic changes in cortical activity. However, our results show that, although BMI training leads to a significant increase of movement information in the sensorimotor cortex, the training significantly increases pain. On the other hand, BMI training to associate the prosthetic hand with the intact hand representation reduces pain with decreased information about phantom hand movements. These results suggest a causative relationship between sensorimotor cortical plasticity and pain.n=9) and amputation of the right forearm  in which patients were instructed to try to move their phantom hands to be in the posture of grasping or opening according to given instructions 16. The pz-scores of the selected MEG sensorsn=10), which was significantly greater than the accuracies for classifying the same signals with randomly relabelled movement types =2.79, two-tailed Student's t-test, n=10; A nested 10-fold cross-validationn=10), which exceeded the accuracies of randomized movement types =5.83, two-tailed Student's t-test, n=10; n=10, P=0.13, Bonferroni-corrected, t(18)=1.57, two-tailed Student's t-test), although the electromyographic signals of the affected hands were not comparable to those of the intact hands z-scored cortical currents were compared between two types of movements with a one-way analysis of variance (ANOVA) for each vertex. The F-value of the ANOVA was averaged for the 10 patients and colour-coded on the normalized brain surface. F-values =5.52, one-way ANOVA; n=10, P=0.007, Bonferroni-corrected, t(18)=3.06, two-tailed Student's t-test; n=10, P=0.00017, Bonferroni-corrected, t(18)=4.72, two-tailed Student's t-test; In all patients, the classification accuracies varied significantly between each side of the sensorimotor cortex for the movements of the real and phantom hands =0.93, two-tailed Student's t-test). Moreover, the classification accuracies of the phantom movements before BMI training were not significantly different in any experiment =0.29, one-way ANOVA; The classification accuracy using the cortical currents contralateral to the moved hand was not significantly different between the phantom hand and real hand =3.51, paired Student's t-test), whereas the total scores of the SF-MPQ2 did not significantly increase, changing from 20.4±15.2 to 23.8±17.1 .For each offline task, the patients . After Br cortex . Surprisn=10). After BMI training, the F-value of the contralateral sensorimotor cortex did not increase, although the patient was instructed in the same way as during the first experiment =0.77, paired Student's t-test) and from 21.2±19.9 to 23.1±20.8 in total scores of the SF-MPQ2 . Notably, the order of the two experiments was random =2.60, paired Student's t-test). Similarly, the total scores of the SF-MPQ2 significantly decreased from 26.0±21.0 to 20.7±16.3 . The F-values of the intact hand movements decreased for the sensorimotor cortex contralateral to the intact hand  were compared among the training sessions =11.5, one-way ANOVA; n=10, P=0.025 and 0.0003, uncorrected, t(18)=2.45 and 4.36, respectively, two-tailed Student's t-test). In contrast, the VAS scores increased significantly after training with the phantom decoder compared with the random decoder =2.62, two-tailed Student's t-test). Notably, these increased scores from the phantom decoder spontaneously returned to the previous state after more than 2 weeks and were not significantly different from the scores before the training =0.63, paired Student's t-test).The above analyses showed that the increases in the pain VAS scores were significantly changed depending on the decoder type  was compared with the increase in the VAS scores (ΔVAS). The correlation coefficients between ΔF and ΔVAS at each of the vertices were colour-coded on the normalized brain  was compared with the increase in VAS scores (ΔVAS). No significant correlation was found between ΔVAS and Δcurrent for the sensorimotor cortex =5.86, one-way ANOVA; n=10, P=0.001 and 0.0034, uncorrected, respectively, Mann–Whitney U-test). However, the alterations of scores were not significantly different between the phantom decoder and random decoder . Among the four types of subscores in the SF-MPQ2, only the continuous pain scores varied significantly among the decoders =7.12; intermittent, P=0.15, F=2.07; neuropathic, P=0.090, F=2.63; affective, P=0.064, F=3.04, one-way ANOVA; n=10, P=0.001 and 0.045, uncorrected, respectively, Mann–Whitney U-test). The alterations of the continuous scores were not significantly different between the phantom decoder and random decoder .Moreover, the total scores of the SF-MPQ2 varied significantly depending on the decoders =17.52, one-way ANOVA; n=10, P=0.00004 and 0.006, Bonferroni-corrected, t(18)=7.44 and 3.59, respectively, two-tailed Student's t-test). Moreover, the classification accuracy increased significantly after training with the phantom decoder compared with the random decoder =3.60, two-tailed Student's t-test). In contrast, the accuracies using the currents for the sensorimotor cortex ipsilateral to the phantom hand did not significantly change among the three types of decoders =1.45, one-way ANOVA; n=10, P>0.05 for each, Bonferroni-corrected, two-tailed Student's t-test; In addition to the univariate analyses, we evaluated the alteration in the cortical currents using the decoding method . For all patients, we compared the accuracies for classifying the phantom movements using the estimated currents in the sensorimotor cortex contralateral and ipsilateral to the phantom hand. The differences in accuracies varied significantly among the three conditions using the currents contralateral to the phantom hand , but not with accuracy using ipsilateral currents .The changes in the VAS scores were significantly correlated with the changes in classification accuracy using the currents for the sensorimotor cortex contralateral to the phantom hand  of the sensorimotor cortex underlaid the effect on the pain. Pain increased significantly in direct proportion to the decoded information content of phantom hand movements; in turn, subsequent training of phantom hand movements based on the intact hand disrupted the information content of the contralateral sensorimotor cortex and led to an improvement in pain. These results are consistent with a probable causal relationship between cortical sensorimotor plasticity and phantom limb pain.Notably, our results demonstrated that pain was not reduced by the reconstruction of motor function; instead, it was changed by plastic changes in the cortical representation. The reconstruction of motor function does not necessarily reverse a putatively maladaptive cortical representation, which was expected from the naive hypothesis. By selecting the decoded information to control the BMI neuroprosthesis, we induced plasticity in the cortical information representation of phantom hand movements (as opposed to simple topographic plasticity) and explored the relationship with painIt is well established that cortical activity representing phantom hand movements is preserved in the sensorimotor cortex1414Our approach provides an interventional method to induce localized changes in cortical representations and to directly and reversibly study the relationship with pain. The MEG signals during the offline task were decoded with accuracy comparable to that of previous work, demonstrating the successful online control of a robotic hand with accuracy greater than that of chanceAs the patients were unaware of the experimental manipulation in each case, it is unlikely that placebo effects were dominant. Other potential aspects of BMI neuroprosthetic control, such as a nonspecific training effect or emotional pain modulation by perceived task difficulty9The estimation of cortical currents from the MEG signals and the decoding method applied to the estimated cortical currents revealed that the information about hand movements was evaluated differentially in both hemispheres. The information of the phantom hand was significantly lateralized to the sensorimotor cortex contralateral to the affected hand. In addition, the alteration of information due to the BMI training was significant only in the contralateral hemisphere. Moreover, for the same contralateral hemisphere, the information of the hand movements was significantly different among the phantom hand and intact hand. The information of intact hand movement was not significantly different after training with the real hand decoder. These results strongly suggest that the BMI training in this study altered the information of the phantom hand movement in the contralateral hemisphere significantly enough to change the pain. However, a recent study suggested the that ipsilateral hemisphere may affect the painResearchers have proposed an incongruence hypothesis of pain3536Our results show that BMI training may be useful as a novel interventional tool to study functional anatomy in the brain. It induces functionally specific plastic changes in the targeted cortex based on the information represented in the activity. Moreover, this method can be easily applied to patients in non-invasive, randomized and blinded studies. These features distinguish this method from other non-invasive interventional tools, such as transcranial direct current stimulationBMI neurofeedback might be a potential novel therapy for phantom limb pain. A previous study showed that the effective rate of mirror therapy was limitedIn addition, the results clearly indicate that we should consider pain as a potential complication when using BMIs for paralysed patients. That is, we must consider the fact that true decoding that increases pain creates a problem for those patients using BMI-controlled robotic prostheses. One possible solution, according to the incongruence hypothesis, would be BMI training accompanied by sensory feedback  patients and one amputee  all of whom had pain in their phantom limb participated in this study . We had 6et al.Our patient group included one amputee and nine BPRA patients with complete avulsion of roots from C5 to Th2. According to Flor For the MEG recording, subjects were in the supine position with the head centred in the gantry. A projection screen in front of the face presented visual stimuli using a visual stimulus presentation system  and a liquid crystal projector  after passing through an optical isolation circuit. The signals for the 84 selected channels were used for offline analysis and online control of the prosthesis. Subjects were instructed not to move their head to avoid motion artefacts. A cushion was placed under the intact elbows to reduce motion artefacts.Five head marker coils were attached to the subject's face before beginning the MEG recording to provide the position and orientation of MEG sensors relative to the head. The positions of the five marker coils were measured to evaluate the differences in the head position before and after each MEG recording. The maximum acceptable difference was 5 mm.We also recorded electromyograms of the face and forearm to monitor muscle activities . SubjectAll patients participated in a crossover trial consisting of three experiments on different days. Each experiment consisted of three tasks: offline task (pre-BMI), BMI training and offline task  was adopted to calculate the decoding parameters and for online prosthetic hand control. First, MEG signals from the 84 selected sensors in the offline session were averaged in a 500-ms time window and converted to the z-scored signals in the offline session were used to train the online decoder, which consisted of an onset detector and class decoder to control the prosthetic hand online in the following BMI training session. The class decoder was trained at the peak classification accuracy of the offline task. The onset detector was trained using the time-averaged signals of 500-ms windows slid by 100 ms from −500 to 1,000 ms, with respect to the timing of the instruction to move. The details of the construction of the decoder are available in our previous reportThe Here we constructed three types of online decoders depending on the data used to train the decoder. The phantom decoder was trained by the MEG signals of the offline task to move the phantom hand. The random decoder was trained by the MEG signals of the same offline task with randomized types of movements. The real hand decoder was trained by the MEG signals of the offline task to move the intact hand.Classification accuracy of the movement type was estimated by 10-fold nested cross-validation, which was adopted so that hyperparameters for the SVM and time window were always selected independently from the testing data set  using the Freesurfer software (Martinos Center Software)VBMEG is a free software for estimating cortical currents from MEG data 51The code used in this study is available by contacting the corresponding author (T.Y.).The data that support the findings of this study are available on request from the corresponding author (T.Y.). The data are not publicly available because they contain information that could compromise research participants' privacy and/or consent.How to cite this article: Yanagisawa, T. et al. Induced sensorimotor brain plasticity controls pain in phantom limb patients. Nat. Commun.7, 13209 doi: 10.1038/ncomms13209 (2016).Supplementary Figures 1 – 6 and Supplementary Tables 1 – 3This movie shows how the patient controlled the prosthetic hand during the BMI training. The patient freely controlled the prosthetic hand to grasp and release a ball by intending to move his phantom hand while watching the movements of the prosthetic hand.


In palliative care, administration of opioids is often indispensable for pain treatment. Pain assessment may help recognize pain and guide treatment in non-communicative patients. In the Netherlands the Rotterdam Elderly Pain Observation Scale (REPOS) is recommended to this aim, but not yet validated. Therefore the objective of this study was to validate the REPOS in non-communicative or unconscious end-of-life patients.In this observational study, the primary researcher applied the REPOS, while both the researcher and a nurse applied the Numeric Rating Scale (NRS). If possible, the patient in question applied the NRS as well. The NRS scores were compared with the REPOS scores to determine concurrent validity. REPOS scores obtained before and after a pain-reducing intervention were analysed to establish the scale’s sensitivity to change.p < 0.001). Optimal sensitivity (0.81) and specificity (0.62) were found at cut-off score 3.A total of 183 REPOS observations in 100 patients were analysed. Almost 90% of patients had an advanced malignancy; observations were done a median of 3 days (IQR 1 to 13) before death. Internal consistency of the REPOS was 0.73. The Pearson product moment correlation coefficient ranged from 0.64 to 0.80 between REPOS and NRS scores. REPOS scores declined with median 2 points (IQR 1 to 4) after a pain-reducing intervention  contains supplementary material, which is available to authorized users. Several studies reported that 45% to 70% of patients with incurable cancer, either admitted to a hospice or staying elsewhere, suffer moderate to severe pain –3. FortyPatients’ self-report of pain is considered the “gold standard” for pain assessment . HoweverProxy assessment often underestimates the pain level, with consequent risk of under treatment , 13. TheWe previously developed the Rotterdam Elderly Pain Observation Scale  and the discharge rate was 4% . Dutch pThe Rotterdam Elderly Pain Observations Scale (REPOS) consists of 10 behavioural items  trained nurses in Laurens Cadenza to assess pain with the REPOS, since at that time symptom measurement was not a standard of care. Firstly, the primary investigator performed 10 bedside observations simultaneously with an experienced REPOS observer, to ascertain sufficient interrater reliability for her. As Cohen’s kappa for the primary investigator was established at 0.76, she was qualified to perform REPOS observations in this study. November–December 2010, NRS and REPOS assessments were implemented in daily practice for all non-communicative or unresponsive patients. All trained nurses achieved good interrater reliability with the primary investigator after 6 to 10 paired observations .Second, from January 2011 to May 2012, the primary investigator or a trained nurse assigned a REPOS score and an NRS-observer score in daily practice as standard of care.Third, from February to June 2013, the second investigator (A.B.) was called in when a patient received a pain-reducing intervention and assigned a REPOS score just before and at least one hour after this intervention. These pre- and post-intervention data were used for the sensitivity-to-change analysis.To determine internal consistency, concurrent validity and the optimal cut-off score, all REPOS observations made during the three different phases were included, with the exception that regarding the training phase only the observations by the primary investigator were selected and not those of the nurses in training. For the sensitivity-to-change analysis only the pre- and post-intervention data from phase three were used.The type of pain assessment (REPOS observation or self-report) depended on the patient’s ability to communicate. In the case of non-communicative or unresponsive patients, the primary investigator assigned a REPOS score and a NRS (NRS-observer), and also the caregiving nurse assigned a NRS score (NRS-proxy). Communicative patients reported in addition to the REPOS score an NRS score themselves (NRS-patient).Demographic characteristics  were extracted from the electronic medical records; the primary diagnoses and the number of comorbidities were evaluated. The primary diagnoses refer to the WHO’s International Classification of Diseases (ICD-10 classification) coding for the patient’s terminal illness.Analgesics prescribed at the time of observation were retrieved from the patients’ medical file and classified according to the WHO three-step pain ladder as step 1 , step 2 (weak opioids) and step 3 (strong opioids) , 29. TheData are presented as mean  in case of normally distributed variables and as median (interquartile range = IQR or minimum-maximum range = range) in case of non-normally distributed variables.To determine interrater reliability, Cohen’s kappa was applied for the primary and second investigator and for all nurses who assigned REPOS scores, and defined as good if ≥ 0.65 .Cronbach’s alpha coefficient served to examine the internal consistency reliability of the REPOS items; a value of at least 0.70 is considered good reliability , 32. PeaThe correlations between the REPOS, NRS proxy and NRS observer in a repeated measurements setting were calculated with linear mixed modelling using the method proposed by Hamlett et al. . In the Data analyses were performed using IBM SPSS Statistics 24. A significance level of 0.05 (two-sided) was used for statistical tests.Over the three study phases, 194 REPOS scores were assigned to 103 patients. Data from three patients were excluded from analysis because these observations were not considered end-of-life assessments: one patient had been discharged after the observations were made and in two data had been obtained earlier than three months before death. Data of the remaining 100 patients were included in the analysis. For those included patients, the first (or only) observation was done a median of 3 days (IQR 1 to 13) before death. The median age was 77 years (IQR 67 to 85), 65% were female, and the median duration of admission was 28 days (IQR 9 to 51). Advanced malignancy, mainly of digestive and respiratory organs, was the main reason for admission (89% of patients). Most patients (73%) were receiving a standing dose of strong opioids combined with a rescue prescription for breakthrough pain. Six percent of all patients had an ‘as needed’ opioids prescription only, and 11% received no analgesics at all. Patient characteristics are shown in Table The number of REPOS observations for the 100 patients included in the analysis was 183. The REPOS has been applied once in 52 patients and twice or more (range between 2 and 13) in 46. The observations were conducted by the observer when caregivers provided care, i.e. 34% during washing or dressing, 30% during posture change, 21% during rest, 9% during a transfer, and 6% in other care situations.The median REPOS score was 3 IQR 1 to 5); the median NRS-observer, NRS-proxy and NRS-patient scores were 2 (IQR 0 to 4), 3 (IQR 1 to 6) and 6 (IQR 2 to 7), respectively. REPOS scores indicative of pain (3 to 10) were assigned in 55% (101/183) of observations. Pain was rated moderate to severe (NRS 4 to 10) in 30% to 67% of NRS scores. All 10 REPOS items were scored as present more frequently in association with NRS scores 4 to 10 than in association with lower NRS scores  to 0.80 (95% CI 0.72 to 0.86) Table . Linear Deleting the above-mentioned 4 items with low correlations for internal consistency had hardly any effect on the Pearson coefficients, which then ranged from 0.62 (95% CI 0.49 to 0.73) to 0.80 (95% CI 0.72 to 0.86).Twenty-two pairs of before-and-after scores were included for the sensitivity-to-change analysis. Twenty-one concerned a pharmacological pain-reducing intervention; the other pair concerned changing the patient’s posture to relieve or prevent pressure sores.p < 0.001). The percentage of REPOS scores indicating no pain (score 0 to 2) increased from 9% (2/22) to 68% (15/22).The median REPOS score declined after a pain-reducing intervention, both pharmacological and non-pharmacological, from 4 (IQR 3 to 6) to 1 (IQR 1 to 3) with a median reduction of 2 points (IQR 1 to 3). This change was statistically significant , is displayed in Fig. In 21% (23/107) of observations the REPOS score was indicative for pain (score 3–10) whereas the NRS-proxy score was not; suggesting false-positive outcomes of the REPOS. In contrast, in 8% (9/107) of observations the REPOS score did not indicate pain (score 0–2) whereas the NRS-proxy score did (score 4–10), suggesting false-negative outcomes.The findings from this study show that the REPOS has promising psychometric properties to assess pain in non-communicative end-of-life patients; including adequate internal consistency, sufficient concurrent validity and good sensitivity to change after a pain-reducing intervention.A variety of observational pain scales have been developed for other settings where non-communicative patients are treated, including intensive care units  and nursThe overall internal consistency of the REPOS in the present study was adequate as judged from the Cronbach’s alpha coefficient of 0.73 , 32. AltWith respect to concurrent validity, a high correlation (0.73) was found – not surprisingly – between REPOS and NRS scores assigned by the same person. The correlation between REPOS and the gold standard (NRS-patient) was only moderate , as is sIt is not unexpected that the REPOS score and the NRS-proxy score may differ to some extent. A high REPOS score combined with a lower NRS-proxy score, or a so-called false positive score, is typically seen in patients who show “emotional” behaviour not related to pain, but based on anger, fear or agitation , 40. TheThis study showed that the cut-off score of 3 or higher is applicable for non-communicative end-of-life patients. However, application of a ‘one-fits-all’ cut-off score is debated , 43. A rA strength of the present study is that most observations were done within the last two weeks of life and therefore including even those patients near the time of death. In the previous validation study of the REPOS , only a Some limitations of this study have to be addressed, however. First, this is a single-centre study in mainly advanced cancer patients and care must be exercised in extrapolating the findings to other settings and patients populations, like palliative home care or community-based palliative care. Nevertheless, it seems unlikely that pain behaviour would be different in a different palliative environment. Second, the sensitivity-to-change analysis concerned only a relatively small sample. This limitation is encountered in many other psychometric studies, seeing that researchers often are not available when patients receive additional analgesia and also because nurses may tend to forego reassessment after a pain-reducing intervention . The comIn conclusion, the REPOS seems to meet the criteria for the use of a pain measurement tool in palliative care of the Expert Working Group of the European Association of Palliative Care (EAPC) . That isAdditional file 1:Rotterdam Elderly Pain Observation Scale (REPOS) score form. (PDF 638 kb)Additional file 2:Rotterdam Elderly Pain Observation Scale (REPOS) instruction chart. (PDF 962 kb)Additional file 3:Rotterdam Elderly Pain Observation Scale (REPOS) decision tree. (PDF 787 kb)


Objective To ascertain long term cardiovascular outcomes in patients whose chest pain remained undiagnosed six months after first presentation.Design Cohort study.Setting UK electronic health record database (CALIBER) linking primary care, secondary care, coronary registry, and death registry information.Participants 172 180 adults aged ≥18 from 223 general practices presenting with a first episode of recorded chest pain, classified from medical records as diagnosed (non-coronary condition or angina) or undiagnosed (cause unattributed) at first consultation between 2002 and 2009 and with no previous record of cardiovascular disease.Main outcome measures Fatal or non-fatal cardiovascular events over 5.5 years’ follow-up. Adjustments were made for age, sex, deprivation, body mass index, smoking status, year of index presentation, and previous records of diabetes or hypertension or previous prescriptions for lipid lowering drugs.Results At the index presentation, 72.4% of patients (124 688) did not have a cause attributed for their chest pain; 118 687 (95.2%) of these did not receive any type of cardiovascular diagnosis over the next six months. Only a minority of patients in all three groups (non-coronary 2.0% (769 of 39 232); unattributed 11.7% (14 582 of 124 688); angina 31.5% (2606 of 8260)) had a recorded cardiac diagnostic investigation in the first six months after presentation. The long term incidence of cardiovascular events was higher in those whose chest pain remained unattributed after six months  compared with patients with an initial diagnosis of non-coronary pain  ; for 3-5.5 years: 1.21, 1.08 to 1.37). Owing to the larger number of patients in the unattributed group, there were more excess myocardial infarctions in the long term in this group (214 more than expected based on the rate in the non-coronary group) than in the angina group (132 more than expected). Patients who had cardiac diagnostic investigations in the first six months had a higher long term risk of cardiovascular events, regardless of the initial chest pain label. Incidence of unattributed chest pain and angina decreased between 2002  and 2009 , but the incidence of chest pain attributed to a non-coronary cause remained stable (37-40 per 10 000 person years). Risk of cardiovascular events did not change over time.Conclusions Most patients with first onset chest pain do not have a diagnosis recorded at presentation or in the subsequent six months, including those who undergo cardiac investigations. These patients have an increased risk of cardiovascular events for at least five years. Efforts to better assess and reduce the cardiovascular risk of such patients are warranted. Each year 1-2% of adults in the UK attend primary care with chest pain symptoms for the first time.Cardiovascular disease will be diagnosed in 2-10% of patients in the unattributed group within 12 months, most within 6-12 weeks of that first presentation.Two important questions remain unanswered. Firstly, do patients who still have unattributed chest pain after an initial period to resolve diagnostic uncertainty have an increased risk of long term fatal and non-fatal cardiovascular events compared with patients diagnosed as having non-coronary chest pain? No study has investigated cardiovascular outcomes in patients with chest pain who remain without a diagnosis of cardiovascular disease, after allowing time for further assessment and short term increases in clinical manifestations of underlying disease. Thus, whether the initial GP diagnosis and investigation provides enough information about disease status to warrant long term monitoring, is unclear.Secondly, has improved access to diagnostic procedures (such as the introduction of rapid access chest pain clinics) and the observed decrease in the population incidence of coronary heart diseaseWe sought to tackle these questions by studying patients with no record of previous cardiovascular disease, who consulted and were recorded with first onset of chest pain in UK primary care but were not given an immediate diagnosis of myocardial infarction. We used primary care electronic health records linked to hospital, disease registry, and cause specific mortality records to obtain a more complete and accurate evaluation of major cardiovascular disease endpoints.www.caliberresearch.org.The study was set in the CALIBER  research programme. CALIBER links primary care data from the Clinical Practice Research Datalink (CPRD) to the national registry of acute coronary syndromes , inpatient diagnoses and procedures from Hospital Episode Statistics, and cause specific mortality from the Office for National Statistics.The study population was all patients in the database aged 18 or over with a first (incident) coded record of chest pain  in primary or secondary care between 2002 and 2009. We excluded those with a record of angina or cardiovascular disease before their first recorded presentation of chest pain in that period or with less than two years of up-to-standard quality data in the CPRD at the time of their first chest pain event. The first record of chest pain was defined as the index presentation.www.keele.ac.uk/mrr) through consensus work to define unattributed chest pain  and non-coronary chest pain . Read codes record morbidity in UK primary care;We identified Read and ICD-10 symptom codes , smoking status, neighbourhood deprivation, prescriptions for lipid lowering drugs, and specific comorbidities) for their association with type of recorded chest pain and as potential confounders for the relation between type of chest pain and future cardiovascular disease. BMI and smoking were defined as the closest recorded value before the index date. Deprivation was based on the English index of multiple deprivation 2007 (IMD)We determined the prevalence of cardiac diagnostic investigations , echocardiography , and myocardial perfusion scans) in the first six months after the index date. As a measure of clinical intervention to reduce risk of future cardiovascular disease, we identified prescriptions for lipid lowering, hypertension, and diabetic drugs in the six months after the index presentation up to the first cardiovascular episode or six months, whichever was earlier. Prescriptions for nitrates were not included because they were used to define angina and were regarded as treating a symptom rather than reducing risk.We assessed two primary outcomes from index presentation to a maximum follow-up of 5.5 years: incident myocardial infarction  in all patients and any recorded first fatal or non-fatal cardiovascular event in patients with unattributed or non-coronary chest pain. We identified cardiovascular events in the “diagnostic window” of the first six months after index presentation; the next five years was the period of observation for the long term outcomes, which are the main focus of this paper.Cardiovascular events were defined as: fatal or non-fatal acute myocardial infarction, angina, coronary heart disease not otherwise specified, heart failure, ventricular arrhythmia, cardiac arrest, ischaemic stroke, haemorrhagic stroke, stroke type not specified, transient ischaemic attack, peripheral arterial disease, abdominal aortic aneurysm, sudden cardiac death, percutaneous coronary intervention, and coronary artery bypass graft surgery. We identified these from primary and secondary care records, MINAP, and the ONS death registry, using previously derived algorithms in CALIBER.We compared the prevalence of baseline cardiovascular risk factors in the three index groups  using multinomial logistic regression, further adjusting for year of index presentation and stratifying by age (<65 or ≥65 years). We determined the percentage of patients in each group with a potential alternative explanation for their chest pain.We compared the incidence of cardiovascular events between groups in two ways. First we derived Kaplan-Meier curves and crude incidence rates from index presentation to 5.5 years. These, therefore, include events during the initial six month diagnostic period as well as long term outcomes.Our second, and main, analysis determined the incidence of cardiovascular events in those not diagnosed as having cardiovascular disease in the first six months—that is, the long term prognosis from six months to 5.5 years. Analysis in the unattributed and non-coronary groups was restricted to those with no cardiovascular diagnosis or recorded angina in the first six months and with follow-up data that included at least the first six months. We used Cox proportional hazards regression to determine the risk of long term cardiovascular event by type of chest pain at baseline, adjusting for baseline covariates and year of index presentation. Analysis for the outcome of myocardial infarction included those who presented initially with angina but had no other cardiovascular event in the first six months.The proportional hazards assumption was assessed using Schoenfeld residuals and deemed adequate for the outcome of myocardial infarction. However, for the outcome of any cardiovascular event, the assumption seemed to be violated, so the follow-up time was split into three periods: six months to one year after initial presentation , one to three years after initial presentation (in those with no cardiovascular event by one year of follow-up), and three to 5.5 years after the index presentation (in those with no cardiovascular event after three years of follow-up). This seemed to give a better model fit than including a (linear) interaction with time or splitting at other time points. Patients were censored by death, end of follow-up period, or end of records in CALIBER.We repeated the main analysis in the subgroup of patients who had no record of diagnostic investigations within the first six months.Finally, we calculated the incidence of new presentations of chest pain for each year from 2002 to 2009. The denominator population for each year was the registered population with at least two previous years of up-to-standard quality data. Annual total incidence rates were directly standardised by applying incidence rates to the age-sex general population structure of England in 2009. However, as this made little difference to the incidence figures, we used crude rates to compare across time.Robust variance estimators were used in all multivariable analyses, accounting for clustering within general practices. We conducted sensitivity analyses for missing data on the baseline covariates. Analysis was performed using SPSS v.21 and Stata/MP 13.0 for Windows.No patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community.The denominator population ranged from 1 158 755 in 2002 to 1 417 211 in 2009. Of these, 172 180 patients from 223 general practices fulfilled the inclusion criteria between 2002 and 2009, with a mean age of 49.0 (SD 17.59). On index presentation, chest pain was recorded as unattributed in 124 688 patients (72.4%), as non-coronary in 39 232 (22.8%), and as angina in 8260 (4.8%). The index presentation was recorded in primary care for 93.5% (160 911) of patients—39 114 in the non-coronary group (99.7%), 115 602 in the unattributed group (92.7%), and 6195 in the group with angina (75.0%). Fewer than 20% of the patients with new recorded unattributed or non-coronary chest pain were aged over 65 , compared with 58.5% (4828) of patients with new angina  was 3.3 years (interquartile range 1.6-5.4). At least six months’ follow-up was available for 151 317 (92.3%) patients, and 40 010 (24.4%) patients had the full 5.5 years of follow-up. Kaplan-Meier curves (fig 1Median times to first cardiovascular event were 135 days (interquartile range 22-664) for patients with unattributed chest pain and 665 (248-1165) days for those with non-coronary chest pain. Rates of cardiovascular events were higher in the unattributed group (292 per 10 000 person years) than in those in the non-coronary group (107 per 10 000 person years) (see appendix table 2). Patients with unattributed chest pain also had a higher rate of myocardial infarction (46 per 10 000 person years) than those with non-coronary chest pain (17 per 10 000 person years) but a lower rate than for those initially recorded with angina (244 per 10 000 person years). Because of the higher number of patients with initially unattributed chest pain, two thirds of myocardial infarctions were in this group . Risk of cardiovascular disease was not statistically significantly different by year of index presentation.In the first six months after the index date, 2.0% (769) of those recorded with non-coronary chest pain (39 232) and 11.7% (14 582) of those with unattributed chest pain (124 668) had a diagnostic investigation (fig 2), compared with 31.5% (2606) of those recorded with angina (8260). Cardiovascular events were recorded in 4.8% (6001) of those with unattributed chest pain and 0.7% (268) of those with initial non-coronary chest pain. Myocardial infarction was recorded in 4.6% (383) of those with initially recorded angina, 0.7% (862) of those with unattributed chest pain, and 0.1% (39) of those with non-coronary pain.v 132), when comparing age and sex specific rates of myocardial infarctions to the non-coronary group.Of the 115 014 patients with unattributed chest pain who were followed up for at least six months, 109 628 (95.3%) remained without a cardiovascular diagnosis at six months . Most cardiovascular events took place in the large unattributed group and represented a 43% excess over expected numbers based on the non-coronary group rate.v 149 per 10 000 for those in the initially unattributed group). Of those with no diagnostic investigation in the first six months, the unattributed group had a higher long term risk of a cardiovascular event (149 per 10 000 person years) than the non-coronary group ) and higher in those without a recorded event who had undergone cardiac investigations (40.1% (261 of 651) v 42.1% (4563 of 10832))  and 26.3% (32 812 of 124 688) in the non-coronary and unattributed groups, respectively. These figures were similar in the subgroup without a recorded cardiovascular event in the first six months (18.1% (6543 of 36 097) Incidence of recorded unattributed chest pain decreased from 124 per 10 000 person years in 2002 to 107 per 10 000 in 2009. Incidence of recorded angina decreased from 13 per 10 000 person years to 5 per 10 000 over the same period  primary care database with linked hospital, myocardial infarction, and death registry data. Estimates of the annual incidence of chest pain over the eight years of the study (15-18 per 1000 person years) were comparable to those from previous analyses of general practice data in the UK.The large group of patients with undiagnosed chest pain in primary care generally do not undergo diagnostic testing but have an increased risk of fatal and non-fatal cardiovascular events for at least five years. More needs to be done to improve the assessment of chest pain in this group and reduce the cardiovascular risk of such patients.Chest pain in primary care is a common diagnostic challenge with potentially serious consequences if cardiovascular disease is missedMost patients presenting with new chest pain in primary care do not have a specific diagnosis recordedSeveral primary care studies show that people presenting with new chest pain and no diagnosis recorded have a higher risk of a cardiovascular event at one year than those with no chest painMost people who present with unattributed chest pain have no diagnosis recorded over the next six months and do not undergo diagnostic testingPatients whose chest pain remains unattributed for six months have higher long term risk of major cardiovascular events than those with an initial non-coronary diagnosis for their chest painBecause of their numbers, patients with unattributed chest pain after six months have the most myocardial infarctions in the long term and should be targeted for better assessment and cardiovascular disease prevention


Complex regional pain syndrome (CRPS) is a debilitating condition affecting the limbs that can be induced by surgery or trauma. This condition can complicate recovery and impair one’s functional and psychological well-being. The wide variety of terminology loosely used to describe CRPS in the past has led to misdiagnosis of this condition, resulting in poor evidence-base regarding the treatment modalities available and their impact. The aim of this review is to report on the recent progress in the understanding of the epidemiology, pathophysiology and treatment of CRPS and to discuss novel approaches in treating this condition. Complex regional pain syndrome (CRPS) is a chronic neurological condition involving the limbs that is characterised by severe pain along with sensory, autonomic, motor and trophic impairment , 2. ThisCRPS is a clinical diagnosis made based on the findings during the history and physical examination of the patient, for which diagnostic criteria including the Orlando Criteria for Complex Regional Pain Syndrome and The Budapest Clinical Diagnostic Criteria for Complex Regional Pain Syndrome by the International Association for the Study of Pain (IASP) have been developed . CRPS caAlthough the diagnostic criteria for CRPS were put forward in 1994, limited data from epidemiological studies are available before 2000. Sandroni et al. conducted the first population-based study of CRPS in 2003, where they reviewed and validated potential cases of CRPS of the local population of Olmsted County over a 10-year period using the IASP and Harden criteria –7. FurthThe development of CRPS following surgery is a major cause of concern as this complicates post-operative management and has significant clinical ramifications. As such, rapid diagnosis and treatment are required to prevent the sequelae such as swelling, atrophy, osteoporosis, pseudo-arthrosis, joint stiffness and tendon adhesions. Operative procedures of the shoulder, distal radius, carpal tunnel and Dupuytren’s contracture have been shown to be associated with the manifestation of CRPS. The incidence of CRPS following shoulder, distal radius, carpal tunnel and Dupuytren’s contracture surgery is estimated to be between 0.9 and 11%, 22 to 39%, 2 to 5% and 4.5 to 40%, respectively , persistent and intense noxious stimulation of peripheral nociceptive neurons results in central sensitisation. Accordingly, there is alteration in nociceptive processing in the CNS and increased excitability of secondary central nociceptive neurons in the spinal cord. This is mediated by the release of neuropeptides such as substance P, bradykinin and glutamate by peripheral nerves, which sensitise and increase the activity of local peripheral and secondary central nociceptive neurons resulting in increased pain from noxious stimuli  and pain in response to non-noxious stimuli  , 32, 33.In the chronic (cold) phase of the clinical course of CRPS, the CRPS-affected limb is cyanosed and clammy as a result of vasoconstriction and sweating. This suggests that excessive sympathetic nervous system outflow is a driving factor in progression of the condition and maintenance of the pain . Animal Variation in the clinical features of CRPS as the condition progresses from the acute (warm) phase to the chronic phase may be attributed to alterations in catecholaminergic mechanisms . During The presence of immunoglobulin G (IgG) autoantibodies against surface antigens on autonomic neurons in the serum of patients with CRPS suggests that autoimmunity may play a role in the development of this condition , 41. ThiNeuroimaging studies of patients with CRPS have demonstrated a decrease in area representing the CRPS-affected limb in the somatosensory cortex compared to the unaffected limb , 44. TheAlthough there is a lack of consensus regarding the influence of genetic factors in CRPS, family studies have suggested a genetic preponderance towards developing this condition. Siblings of CRPS patients under 50 years were at three times higher risk of developing the condition, with a mitochondrial inheritance pattern , 48. FurDue to the prevalence of anxiety and depression in patients with CRPS and the unusual nature of symptoms, psychological factors have been hypothesised to play a role in the development or propagation of CRPS. Puchalski et al. observed a higher occurrence of CRPS following fractures of the distal radius in elderly patients with psychological and/or psychiatric illness, thereby implicating the role of psychological factors . HoweverPhysical and occupational therapy is a key component of the rehabilitation process in patients with CRPS and is recommended as the first-line treatment. Patients can develop kinesophobia and the aim of therapy is to overcome this fear of pain and enable the patient to gain the best functional use of the limb. This program is tailored specifically to each individual and can involve multiple modalities. These include elevation, massage, contrast baths, transcutaneous electrical nerve stimulation, gentle range of motion, isometric strengthening exercise and stress loading of the affected limb along with provision of adequate analgesia. Occupational therapy encourages use of the affected limb in activities of daily living. The use of specialised garments or wrappings may reduce oedema and sensory overload of the affected limb. Mirror box therapy has been shown to reduce neuropathic pain and improve two-point sensation in the affected limb .Chronic pain affects the health-related quality of life and places a huge emotional and psychological burden on patients. Thus, it is essential for newly diagnosed patients with CRPS to have a discussion with a psychological care provider regarding their condition and its progression as well as the need for active self-management and participation in a care plan. This can be followed up with cognitive behavioural therapy, learning relaxation skills and biofeedback to facilitate rehabilitation, reduce pain intensity and provide patients with more control. It is important to assess and treat patients for concomitant axis I disorders such as major depression, generalised anxiety disorder and post-traumatic stress disorder, which may complicate the rehabilitation process.Corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) reduce inflammation and have been used in the treatment of CRPS. Randomised controlled trials (RCTs) and case series have reported significant improvements in pain and range of motion in the affected limb following treatment with both oral and intramuscular corticosteroid regimens –56. HoweN-acetylcysteine have shown success in providing pain relief [The use of anti-oxidants in the treatment of CRPS has been based on the perception that oxygen free radicals generated by the inflammatory process may be a key component of the propagation of the disease process. Topical preparations of anti-oxidants such as dimethyl sulfoxide (DMSO) and n relief , 59. Then relief , 61. Vitn relief , 63.Anti-convulsant drugs such as gabapentin have demonstrated evidence of effectiveness in providing pain relief in acute and chronic neuropathic are commonly used as part of the pharmacological management of CRPS , 65. StuN-methyl-D-aspartic acid (NMDA) as a neurotransmitter [The upregulation of inflammatory pathways in CRPS sensitises excitatory nociceptive pathways that use nsmitter . The cennsmitter –73. Howensmitter .Sympathetically mediated pain in CRPS has led to the studies investigating the role adrenergic receptor antagonists or alpha-2 adrenergic agonists in treating this condition. Phenoxybenzamine has shown success in providing complete pain remission, with increased effectiveness when administered in the acute stage, thus emphasising the importance of early recognition of CRPS , 76. TheSeveral treatment strategies have also been used in managing the chronic stage of CRPS. Calcium-channel blockade with nifedipine has been reported to be effective in managing the vasoconstriction occurring in this phase of CRPS , 79. AddAs CRPS progresses, there is localised bone resorption and remodelling, which can lead to nociceptive bone pain, osteopenia and osteoporosis. In addition, reduction in bone mineral density occurs as a result of lack of use of the affected limb. Calcitonin preserves bone mass, has effects on microvasculature and has anti-nociceptive effects, which have been found to be effective in treating acute and chronic pain –86. BispThere are contrasting views regarding the use of opioid therapy in the treatment of CRPS. While opioid therapy is useful in the acute phase of tissue injury, long-term use for both peripheral and central neuropathic pain is less efficacious and requires larger doses . AlthougThe discovery of autoantibodies against adrenergic receptors suggesting that CRPS has an autoimmune component provides the basis for the use of intravenous immunoglobulin (IVIG), which is a potent anti-inflammatory and immune-modulator , 41. A RAn alternative approach studied involves the use of sympathetic blockade, which has diagnostic and therapeutic benefits. Sympathetic blocks aim to alleviate the sympathetically mediated pain and can be used in combination with botulinum toxin to prolong the duration of analgesia. Recent evidence has shown sympathetic blockade to provide substantial pain reduction as well as longer analgesic duration, which enable patients to improve participation in functional therapies –99. HoweNeuromodulation may also play a role in treating CRPS, especially in patients in unresponsive to sympathetic blockade. One RCT reported SCS and physiotherapy to be significantly more effective at pain relief compared with physiotherapy on its own at 6 months and 2 years although this effectiveness diminished at long-term follow up of 5 years . HoweverSympathectomy can be performed as an extension of temporary sympathetic blockade in patients who have good but transient relief from sympathetic blockade. This involves severing the sympathetic chains or stellate ganglion using chemicals, radiofrequency or open surgical techniques to prolong analgesia. Chemical sympathectomy is carried out using alcohol or phenol injections to destroy the sympathetic chain but this method has variable outcomes with limited evidence to support its effectiveness . RadiofrAmputation in CRPS may be indicated due to pain, limb dysfunction, gangrene, infection or ulcers . The majChronic regional and neurogenic inflammation are thought to play a key role in the initiation and propagation of CRPS , 109. PaThe anti-nociceptive effect of hyperbaric oxygen therapy (HBOT) has been well-documented in animal models. This is conferred via neural nitric oxide-dependent release of the endogenous opioid, dynorphin, which subsequently activates k- and μ-opioid receptors . A RCT wBTX-A has been shown to confer pain relief in neuropathic pain, which complicates disorders of the central and peripheral nervous system and may therefore demonstrate efficacy in managing CRPS. Kharkar et al. investigated the efficacy of BTX-A in providing pain relief in 37 subjects with CRPS suffering from focal tonic dystonia . In thisRecent developments in the understanding of the autoimmune aetiology of CRPS have highlighted the potential use of plasma exchange therapy, which has demonstrated benefit in other autoimmune disorders. A retrospective case series of 33 patients with CRPS receiving plasma exchange was conducted by Aradillas et al. to assess this approach . In thisAs our understanding of the pathophysiology of CRPS continues to grow, so too does the scope for the finding of new or existing agents to target the different disease mechanisms. The neurogenic inflammation that occurs in CRPS can be attributed in part to the activation of microglia, which is mediated by Toll-like receptor (TLR) signalling. Naltrexone has antagonistic effects at the TLR-4 and hypothetically suppress inflammation. A recent case series of two patients found low-dose naltrexone to be effective in reducing pain with minimal side effects and a RCT is currently ongoing to investigate this further , 119.In neuropathic pain models, activated microglia express cannabinoid receptor-2 (CB-2) and chemokine fractalkine receptor (CX3CR1) , 121. BoNSAIDs and corticosteroids have been used in CRPS with the aim of limiting pain and inflammation. The novel anti-inflammatory agent, polydeoxyribonucleotide is a low molecular weight deoxyribonucleic acid complex that acts as a selective agonist against the adenosine A2A receptor. This leads to a decrease in the secretion of inflammatory cytokines such as TNF-α, macrophage inflammatory protein 1α and IL-6 along with an increase in IL-10 . FurtherAlthough there has yet to be a successful treatment for CRPS to date, years of research have provided us with many valuable lessons and our understanding of this condition continues to grow. It is evident that a CRPS population is heterogeneous, with distinct subgroups that exhibit different clinical and biochemical features, thereby exhibiting a varying response to treatment. Moreover, the evidence-base regarding CRPS type II remains scarce in contrast to CRPS type I. Hence, future work is needed to elucidate the subgroups of patients who would benefit the most from currently available treatment. Given the complex nature of this syndrome, it is unlikely that targeting a specific mechanism will be effective. As with other chronic disorders, the future of CRPS treatment may lie in combination therapy and studies investigating this will be necessary.The complex pathophysiology of CRPS remains a challenge for clinicians and researchers alike in developing treatments to successfully combat this severe, life-threatening condition. Due to the multifactorial nature of this condition, animal models that can simulate the disease process are lacking, which is further compounded by our limited understanding of the mechanisms involved. This has hindered the development of new therapies, leading clinicians to adopt a trial and error approach towards managing this syndrome. Hence, the majority of studies evaluating novel approaches have been restricted to case series or small pilot studies. The recent declaration by the United States Food and Drug Administration of CRPS as an official disease has given us renewed hope, as this has been a catalyst for new drug development.


Pain is suboptimally managed in patients with cancer. We aimed to compare the effect of a policy of adding a clinician-delivered bedside pain assessment and management tool (Edinburgh Pain Assessment and management Tool [EPAT]) to usual care (UC) versus UC alone on pain outcomes.In a two-arm, parallel group, cluster randomized (1:1) trial, we observed pain outcomes in 19 cancer centers in the United Kingdom and then randomly assigned the centers to either implement EPAT or to continue UC. The primary outcome was change in the percentage of study participants in each center with a clinically significant (≥ 2 point) improvement in worst pain (using the Brief Pain Inventory Short Form) from admission to 3 to 5 days after admission. Secondary outcomes included quality of analgesic prescribing and opioid-related adverse effects.P = .046) and it increased to 15.4%  when two centers that failed to implement EPAT were excluded. EPAT centers had greater improvements in prescribing practice and in the Brief Pain Inventory Short Form pain subscale score. Other pain and distress outcomes and opioid adverse effects did not differ between EPAT and UC.Ten centers were randomly assigned to EPAT, and nine were assigned to UC. We enrolled 1,921 patients and obtained outcome data from 93% . Participants  had a variety of cancer types. For centers randomly assigned to EPAT, the percentage of participants with a clinically significant improvement in worst pain increased from 47.7% to 54.1%, and for those randomly assigned to continue UC, this percentage decreased from 50.6% to 46.4%. The absolute difference was 10.7% (95% CI, 0.2% to 21.1%; A systematic integrated approach improves pain outcomes for inpatients in cancer centers without increasing opioid adverse effects. We tested EPAT in a single cancer center and found preliminary evidence of its feasibility and efficacy.16Admission to a cancer center provides an important opportunity to improve pain outcomes. We developed a simple clinician-administered bedside tool—the Edinburgh Pain Assessment and management Tool (EPAT)—that builds on the concept of pain as the fifth vital sign.The current study aimed to determine the effectiveness of implementing EPAT in multiple cancer center inpatient units. Specifically, we sought to determine whether the percentage of inpatients with improved pain increased in cancer centers that implemented EPAT compared with cancer centers that continued to deliver usual care (UC). We also aimed to find out whether implementing EPAT improved prescribing practice and whether it increased opioid-related adverse effects.We used a two-arm, parallel group, cluster randomized controlled trial to evaluate the effect on pain outcomes of introducing EPAT into cancer centers . The trial clusters were the inpatient units of regional cancer centers in the United Kingdom. In each center, the trial was conducted in two phases. In the first, pre–random assignment phase, 50 patients with cancer-related pain were enrolled, and their pain outcomes were measured after management in accordance with UC. Centers were then randomly assigned to either implement EPAT (EPAT centers) or to continue providing UC (UC centers). In the second, post–random assignment phase, an additional 50 patients were enrolled and their pain outcomes were measured.Cancer centers were eligible to participate if they did not have an existing bedside pain management system, could recruit 100 patients in the required time frame, and did not anticipate organizational changes that might affect pain management policies. Within each center, patients were eligible to participate if they were adults ( ≥ 18 years of age) with active cancer and cancer-related pain, with a worst pain in the past 24 hours score (assessed within 24 hours of admission) of ≥ 4 on a scale of 0 to 10. The protocol (Data Supplement) lists complete inclusion and exclusion criteria.The trial was approved by the Scotland A Research Ethics Committee and was overseen by a trial steering committee. Conduct of the trial in each center followed study guidance procedures (Data Supplement). All centers and participants provided written informed consent.A database software algorithm, implemented by the Edinburgh Clinical Trials Unit, randomly allocated cancer centers to implement EPAT or continue providing UC in a 1:1 ratio using variable-size permuted blocks. Because of the cluster design, we were unable to mask cancer center clinicians, patients, or data collectors to intervention. However, the clinicians in the UC centers did not know the content of EPAT, and patients self-rated their pain and knew only that their cancer center was taking part in a pain study.All patients admitted to the participating cancer centers were given information about the study. A research nurse obtained patients’ verbal consent to eligibility screening. The nurse provided eligible patients with a further explanation of the study and obtained their written consent for participation. Enrollment was done independently of the clinical team.The clinicians who delivered pain management (EPAT or UC) were oncology nurses, nursing care assistants, oncology trainee doctors, and senior oncologists. In UC centers, the clinical team managed patients’ pain according to their clinical judgment and existing local guidelines. In EPAT centers, the clinical team was provided with the EPAT (Data Supplement) and given brief  training in its use. EPAT was designed to address the aforementioned key barriers to effective pain management by prompting clinicians to systematically assess pain using simple questions that should not be shortened or paraphrased; to follow linked treatment algorithms, rather than broad guidelines, including instructions on opioid prescribing; and to regularly reassess pain and opioid-related adverse effects.EPAT integrates pain assessment into routine care by its inclusion in the patient’s bedside chart. Clinicians are prompted to assess pain using a two-step procedure every time the patient’s vital signs are recorded. In step 1 , the pat17 Worst pain is the recommended outcome measure for trials, and a 2-point change on this item has been found to be meaningful to patients.20The primary trial outcome (measured at the cancer center level) was the change in the percentage of participants with a clinically significant improvement in pain. We defined a clinically significant improvement in pain as a reduction of ≥ 2 points in the severity of worst pain reported over the previous 24 hours measured between admission and reassessment (3 to 5 days after admission). Worst pain is an item on the Brief Pain Inventory Short Form (BPI-SF), which has 11 questions, each rated on a scale of 0 to 10, and is validated for use in the evaluation of cancer pain.21; the mean change in opioid adverse effects 22; the percentage of participants receiving good practice prescribing ; the percentage of participants readmitted to the cancer center with uncontrolled pain within 14 days of discharge; and in EPAT centers, satisfaction with the attention given to pain and the ease of use of EPAT rated on a 0 to 10 scale by patients and nurses, respectively.The secondary trial outcomes  were the percentage of participants with controlled pain (worst pain BPI-SF score < 4); the mean changes in BPI-SF scores ; the mean change in global distress in the past 24 hours using the National Comprehensive Cancer Network thermometer Outcome data were collected from participants, medical records, and relevant staff, and as appropriate, by the research nurses. If participants had been discharged from the cancer center before the time of the follow-up assessment, the research nurse collected the outcome data by telephone.We estimated that two treatment groups of nine cancer centers each, with 100 participants per cancer center  would give 80% power at the 5% significance level to detect a difference of at least 15% between the trial arms in the primary outcome. The main analysis was conducted  at the end of the trial, using an intent-to-treat principle that included all participants who provided usable outcome data.23 For each analysis, we calculated a single summary measure for each cancer center and compared the UC centers with the EPAT centers using a two-sample t test. Hence, the summary statistic for the primary outcome was the difference between the percentage of participants who achieved a clinically significant reduction in pain before random assignment (phase 1) and the percentage who achieved a clinically significant reduction in pain after random assignment (phase 2). For continuous outcome measures, the summary statistic was the difference in the mean score before and after random assignment.Because there were, as planned, relatively few clusters (cancer centers) and little variability in the cluster size, we performed the analyses using summary measures.In a prespecified sensitivity analysis, hierarchical patient-level analyses were performed using random-effects models. The results for the primary end point (achieving a reduction of ≥ 2 points in the severity of worst pain reported over the previous 24 hours) and a secondary end point (the magnitude of the reduction in the severity of worst pain reported over the previous 24 hours) are reported. In addition to the main analysis, we performed a post hoc sensitivity analysis of the primary outcome and of good practice prescribing excluding cancer centers that had been randomly assigned to EPAT but were unable to implement it.The United Kingdom has 40 cancer centers. We selected 20 centers from those eligible to participate, aiming for geographical spread and a range of center sizes. Each center took part in the trial for approximately 1 year (including both pre– and post–random assignment phases). Center participation was staggered and occurred between December 2007 and January 2013. One center dropped out before random assignment. Ten cancer centers were randomly assigned to implement EPAT, and nine were assigned to continue providing UC .Of the 42,000 patients admitted to the cancer centers during the trial, 8,400 were assessed as having moderate or severe pain , and 1,921 patients were enrolled . The most common reason for excluding patients was that their admission was for planned chemotherapy and too brief to allow completion of the protocol. Only 2.7% of eligible patients  declined to participate. Participants had a mean age of 60 years , and 49% were female . PatientP = .046). There was no difference in outcomes between participants assessed by telephone after discharge and those who were assessed as inpatients.Introducing EPAT into cancer centers had an effect on pain outcomes. The percentage of participants with a clinically significant improvement in pain increased after random assignment in eight of the 10 EPAT centers and in three of the nine UC centers . In EPATP = .004). The remaining eight centers that implemented EPAT used it in at least 90% of patient assessments as indicated by entries on the participants’ charts.Two of the centers randomly assigned to implement EPAT were unable to do so because of unanticipated organizational changes. In these centers, the percentage of participants with a clinically significant improvement in pain actually decreased after random assignment . A post Regarding the trial’s secondary outcomes, EPAT centers had greater improvements in good practice prescribing (a difference that was larger when the two centers unable to implement EPAT were excluded) and greater changes in the mean worst pain item and in mean pain subscale scores. However, there were no statistically significant differences between EPAT and UC centers in the percentage of participants with controlled pain, the mean pain interference score, the mean total pain score, or the mean severity of global distress. There was also no difference between EPAT and UC centers in the percentage of patients who had received strong opioids (80%), in the mean total 24-hour oral morphine equivalent (10 mg), or importantly, in opioid-related adverse effects . We wereP = .014). For the corresponding analysis of the magnitude of the reduction in the patients’ worst pain scores, the estimated intracluster correlation coefficient was 0. The estimated treatment effect was 0.82 .From the prespecified patient-level sensitivity analysis of the primary end point, the estimated intracluster correlation coefficient was 0.004, and the estimated treatment effect was 11.6%  improves pain outcomes for patients with moderate or severe cancer-related pain. The difference between EPAT and UC centers in the percentage of patients with a clinically significant reduction in their worst pain was 10.7%. This difference increased to 15.4% when the two centers that had been unable to implement EPAT were excluded. It should be noted, however, that the 95% CI for the 10.7% difference is wide (0.2% to 21.1%).24 This effect would also be expected to decline over the many months of study in centers continuing with UC. The effect was not seen in centers implementing EPAT, which overall had better outcomes.Inspection of the results by cancer center revealed that the difference in the primary outcome between centers delivering EPAT and centers continuing UC reflected not only an improvement in pain management with EPAT (except in the two centers that failed to implement EPAT), but also a deterioration in pain management in most of the centers that continued UC. We did not find any differences in patient or cancer characteristics in the samples studied in each phase that could account for this. Therefore, we suggest that a likely explanation for the deterioration in outcome in some, but not all, of the UC centers in the post–random assignment period reflects a return to pretrial standards of pain management after improvement during the pre–random assignment phase of the trial. This short-term effect on clinicians’ behavior might be expected as a result of awareness that their center was participating in a study that monitored their patients’ pain scores.26 This absence of increased adverse effects despite better pain management may be because EPAT alerts clinicians to monitor adverse effects of pain treatment, as well as efficacy.EPAT centers prescribed analgesics more appropriately (as defined in the Data Supplement) and not in higher doses. Although the concept of pain as the fifth vital sign has been criticized as a potential cause of increased opioid-related adverse effects, the use of EPAT did not increase opioid adverse effects.EPAT did not improve all of the secondary trial outcomes. The percentage of participants with controlled pain, the severity of general distress, and the degree to which pain interfered with activities did not differ between trial arms. The short duration of this study and inpatient setting arguably made it difficult to change these outcomes.27 As expected, the patient-level sensitivity analyses yielded parameter estimates and CIs that were broadly similar to those obtained in the primary cluster-level analyses and with levels of statistical significance that were more extreme.An additional and notable finding is that implementation of EPAT was hampered by organizational and leadership changes in two trial centers, which also subsequently had worse patient outcomes. This observation highlights the importance of organizational factors and leadership, as well as clinician education, in achieving positive changes in patient care.29 Two preliminary studies evaluated the integration of systematic pain management into the usual clinical care delivered by oncology teams with more promising findings.31 Finally, it is notable that published studies of integrated and systematic approaches to the management of other symptoms in patients with cancer, in particular depression, have also found these to be effective.34Previously published smaller studies have evaluated the effects of systematic management for cancer pain. Two randomized trials compared algorithm-based pain management by pain specialists, rather than oncology teams, with variable results.The strengths of this trial include the participation of many cancer centers in the United Kingdom and negligible missing outcome data. However, the trial has limitations. First, the trial was carried out within one particular health care system , although the issues associated with cancer pain assessment and management are similar in most developed countries. Second, we do not have information on participants’ longer term outcomes. Third, oncology teams and those collecting the outcome data from patients could not be masked to the treatment allocation.15 The findings of this trial add to the accumulating evidence for the efficacy of more integrated and systematic approaches to symptom management in patients with cancer.In conclusion, this study is, to our knowledge, the first large randomized evaluation of the integration of systematic pain assessment and management into routine care of patients with cancer. The implementation of EPAT improved both prescribing practice and pain outcomes. Furthermore, it did not increase opioid-related adverse effects. This latter finding is important given concerns that the measurement of pain as a vital sign and linked opioid prescribing can be harmful.


Low back pain is common and associated with a considerable burden to patients and society. There is uncertainty regarding the relative benefit of paracetamol and diclofenac and regarding the additional effect of pain medication compared with advice only in patients with acute low back pain. This trial will assess the effectiveness of paracetamol, diclofenac and placebo for acute low back pain over a period of 4 weeks. Furthermore, this trial will assess the additional effectiveness of paracetamol, diclofenac and placebo compared with advice only for acute low back pain over a period of 4 weeks.The PACE Plus trial is a multi-center, placebo-blinded, superiority randomized controlled trial in primary care, with a follow-up of 12 weeks. Patients with acute low back pain aged 18–60 years presenting in general practice will be included.Patients are randomized into four groups: 1) Advice only ; 2) Advice and paracetamol; 3) Advice and diclofenac; 4) Advice and placebo. The primary outcome is low back pain intensity measured with a numerical rating scale (0–10). Secondary outcomes include compliance to treatment, disability, perceived recovery, costs, adverse reactions, satisfaction, sleep quality, co-interventions and adequacy of blinding.Between group differences for low back pain intensity will be evaluated using a repeated measurements analysis with linear effects models. An economic evaluation will be performed using a cost-effectiveness analysis with low back pain intensity and a cost-utility analysis with quality of life. Explorative analyses will be performed to assess effect modification by predefined variables.Ethical approval has been granted. Trial results will be released to an appropriate peer-viewed journal.This paper presents the design of the PACE Plus trial: a multi-center, placebo-blinded, superiority randomized controlled trial in primary care that will assess the effectiveness of advice only, paracetamol, diclofenac and placebo for acute low back pain.NTR6089, registered September 14th, 2016. Protocol: Version 4, June 2016.Dutch Trial Registration  Low back pain is one of the most common diseases of the musculoskeletal system. It is associated with a considerable burden to patients and society. According to the global burden of disease study, low back pain is the number one disorder responsible for disability in the population ) . The poiClinical guidelines for the management of low back pain have been issued in many countries around the world in order to promote rational care . These gIn July 2014, the first placebo controlled trial of paracetamol for acute low back pain  was published . AustralConsidering the findings in this Randomized-Controlled Trial (RCT), one relevant question is if the current clinical guideline recommendations should be changed regarding the use of paracetamol. The Australian research team stated that replication of their study findings should take place before dismissing paracetamol as a treatment option for low back pain. Changing the content of guidelines based on the findings of a single trial without verification of the results in other similar populations would seem premature . BesidesSecondly, the awareness of the limited clinical effect of paracetamol could easily influence the decision to step up more quickly to using NSAIDs which are the next recommended type of pain medication in the clinical guidelines. Should NSAIDs even be recommended as first analgesic treatment option instead of paracetamol for patients with acute low back pain? NSAIDs have been compared with placebo in patients with low back pain and have shown significantly better results for pain reduction . HoweverThe primary objective of the PACE Plus trial is to compare the clinical effectiveness of paracetamol, diclofenac and placebo for acute low back pain in primary care over 4 weeks of follow-up. Furthermore, this trial aims to determine the added clinical effectiveness of medication and advice  versus advice only for acute low back pain in primary care over 4 weeks of follow-up. Secondary objectives of the PACE Plus trial are to compare disability, patients’ perceived recovery, quality of life, costs, time to recovery, compliance to treatment, adverse reactions, patients’ satisfaction, sleep quality and co-interventions between advice plus paracetamol, advice plus diclofenac, advice plus placebo and advice only groups.The trial will be a four arm, multicenter, placebo-blinded, superiority randomized controlled trial using double dummy technique in general practice with a follow-up period of 12 weeks. The study design and flow of patients in the PACE Plus trial are shown in Fig. The patient eligibility criteria of the PACE trial are similar to the in- and exclusion criteria that will be used in the PACE Plus trial. Based on the figures in the PACE trial, we will need to assess at least 2231 patients to end up with 800 patients that fulfill eligibility criteria and are willing to participate in the trial. In the PACE trial, 4606 patients were screened by 235 primary care providers during a recruitment period of 3.5 years. This comes down to an average of 5.6 patients per primary care provider per year. The PACE Plus trial has a planned recruitment period of 2 years. We thus need cooperation of at least 200 General Practitioners (GPs) for the referral of patients with acute low back pain for screening. Based on the Dutch National Assessment of Diseases in Primary Care , in the Patients will be recruited in Dutch general practices and referred to the PACE Plus research team. Before enrolment in the trial, all potential patients will be assessed for eligibility and informed consent.In order to be eligible to participate in this study, a patient must meet all of the following criteria: 1) Aged between 18 and 60 years; 2) Low back pain of less than 6 weeks duration; 3) Primary complaint of pain in the area between the 12th rib and buttock crease, with or without radiating leg pain; 4) Experiencing a new episode of low back pain, preceded by a period of at least 1 month without low back pain; 5) Low back pain severe enough to cause at least moderate pain ).A potential patient who meets any of the following criteria will be excluded from participation in this study: 1) known or suspected serious spinal pathology ; 2) Currently taking recommended regular doses of analgesics, including paracetamol or diclofenac; 3) Spinal surgery within the preceding 6 months; 4) Serious co-morbidities like severe rheumatoid arthritis, cardiac failure, diabetes preventing prescription of paracetamol  or diclofenac ; use of proton pump inhibitors before inclusion is not an exclusion criterium, as the patient is considered to be protected (patient will have to continue using this medication during use of study medication); 5) Use of coumarine derivatives, clopidogrel, prasugrel, ticagrelor, acetylsalicylacid derivatives, systemic glucocorticoid, selective serotonin reuptake inhibitors (SSRIs), venlafaxine, duloxetine, trazodone, spironolactone or other medications that may interact with paracetamol and/or diclofenac; 6) Known intolerance for paracetamol and/or diclofenac; 7) Pregnant or planning to become pregnant during the treatment period.Patients consulting their GP or doctor’s assistant for low back pain and fulfilling simple referral criteria  and no contraindications for diclofenac) can be referred to the PACE Plus research team. Potential participants will be contacted within 24 h by a researcher for further information about the trial, assessment of the eligibility criteria and collection of informed consent.After collection of informed consent, patients will be randomly allocated to one of four intervention groups: 1 advice only group and 3 medication groups. Randomization will be performed using a two-step process. In the first step, patients will be randomized between ‘advice only’ and ‘medication’ using a computer-generated randomization list. After the first step of the randomization process, patients and GPs will be informed about the outcome of treatment allocation (either that they receive advice only or that they receive blinded study medication).In the advice only group, patients will not get study medication, but receive advice and reassurance from their GP or doctor’s assistant only .For people who are randomized in the first step to ‘medication’, a trial medication prescription will be sent to the Erasmus University Hospital Trial Pharmacy. In the second step of randomization, an independent trial pharmacist will use a randomization list with random blocks to determine the medication group that patients will be randomized to . Both randomization lists used in this two-step process are made by an independent data-manager who is not involved in this trial.Paracetamol group: active oblong tablets (active paracetamol) and placebo round tablets (placebo diclofenac);Diclofenac group: placebo oblong tablets (placebo paracetamol) and active round tablets (active diclofenac);Placebo group: placebo oblong tablets (placebo paracetamol) and placebo round tablets (placebo diclofenac).After allocation to 1 of the 3 medication groups, patients will receive a treatment pack containing large oblong tablets and small round tablets prepared and numbered by an independent trial pharmacist. Treatment packs will be sent by mail to the patient, and are expected to arrive the next day. Using the double dummy technique, active medication differs between groups as follows:The placebo tablets that will be used in the PACE Plus trial are identical in appearance and taste to their active counterparts, but do not contain the active component. All medication packaging will be identical between the 3 medication groups, except for a unique randomization number for each participant. Every package contains a reply paid post envelope, in which unused tablets can be returned for counting after 4 weeks of follow-up. The patient, patient’s GP and pharmacist and researchers involved in data collection and analysis will be blind to treatment group allocation. Unblinding is permissible in case of a reported suspected unexpected serious adverse reaction (SUSAR).All patients in the PACE Plus trial will receive advice and reassurance from either their GP or doctor’s assistant before referral .Paracetamol group: paracetamol (immediate release) 4 daily doses of 1000 mg, placebo diclofenac 2 daily doses.Diclofenac group: diclofenac (immediate release) 2 daily doses of 75 mg, placebo paracetamol 4 daily doses.Placebo group: placebo paracetamol 4 daily doses, placebo diclofenac 2 daily doses.Patients in the medication groups will be asked to take 4 daily doses of 2 oblong tablets and 2 daily doses of 1 round tablet, until they have experienced two consecutive pain free days (NRS 0 or 1 out of 10), or for a maximum of 4 weeks if a pain free interval does not occur. This means that treatment groups will receive the following drug dosages:Allocated treatment as described above may be discontinued by the patient’s own GP in case the patient revisits his or her GP because of persisting low back pain; this will be recorded during follow-up measurements.During participation in the PACE Plus trial, patients in the medication groups will be asked not to take paracetamol or NSAIDs because this may lead to overdose of these medications. Participant’s GP and Pharmacist will be informed about the participation of their patient in the PACE Plus trial, and for the medication groups, the usage of trial medication. Additional medication taken by the patient for low back pain will systematically be recorded in patients’ questionnaires at all follow-up measurements. Physiotherapy as a co-intervention is allowed, but will also be recorded in follow-up measurements.The primary outcome of the PACE Plus trial is low back pain intensity measured with an 11-point NRS . Pain intensity will be recorded daily over a 4 week follow up period.compliance to treatment measured daily by asking ‘How many large, oblong tablets did you take today?’ and ‘How many small, round tablets did you take today?’ (questions derived from the Brief Medication Questionnaire (BMQ) .)disability measured using the Roland Morris Disability Questionnaire  .patients’ perceived recovery measured using a 7-point Likert scale that will be dichotomized into recovered (score 1 ‘complete recovery’ and 2 ‘much improved) and not-recovered (score 3 ‘improvement’ to score 7 ‘worse than ever’).quality of life measured using the EuroQol Group 5 Dimensions, 5 Level Questionnaire (EQ-5D-5 L) .costs; all direct medical and patient costs measured using the iMedical Consumption Questionnaire (iMCQ), and productivity costs measured with iProductivity Cost Questionnaire (iPCQ) , 15.time to recovery assessed using the daily low back pain severity scores. Recovery is defined as the first day of 0 or 1 pain intensity, maintained for seven consecutive days.adverse reactions systematically recorded in the follow-up questionnaires; all reported adverse events will be followed until they have abated or until a stable situation has been reached.patients’ satisfaction measured using an 11-point NRS; score range 0–10, higher score means more satisfaction.sleep quality measured using a 4 point Likert scale derived from the Pittsburgh Sleep Quality Index (PSQI) . Scores co-interventions systematically recorded in the follow-up questionnaires.adequacy of blinding assessed in medication groups by asking patients to which treatment group they believe to be allocated after 12 weeks of follow-up.Secondary outcome measures that are collected in the PACE Plus trial are:gender, age, height, weight, education and occupational status.duration of complaints, history of back complaints, and comorbidity.job satisfaction measured with a 7-point Likert scale (score range from extremely unsatisfied to extremely satisfied).neuropathic pain measured with the Pain DETECT questionnaire  .potentially modifiable prognostic indicators measured with the StarT Back Tool .Baseline characteristics that will be measured in the PACE Plus trial  are:Table For the primary outcome (low back pain intensity (NRS)), between group differences of at least 20% are considered clinically relevant; this difference is expressed in the area under the longitudinal pain trajectories for the four treatment groups. Because low back pain is an episodic condition that is known to fluctuate over time, the correlation between repeated measured was assumed moderate . In the sample size calculation, a statistical power of 84% and a random dropout not exceeding 15% were assumed. With group sizes of 200 patients, a between group difference in low back pain intensity of at least 20% can be detected.The statistical analysis will be performed according to the intention-to treat principle.For clinical effectiveness the between group differences for the primary outcome, low back pain-intensity will be evaluated using a repeated measurements analysis with linear mixed effects models with adequate specification of the fixed and random effects structures to account for possible nonlinear effects. The covariance structure will be unstructured, but we will compare Akaikes’ information criterion between the different covariance structures and choose the structure with the lowest value.A similar approach as described in ‘primary study parameter(s)’ will be used for the continuous secondary outcomes  to assess between group differences.A Cox proportional hazards model will be carried out to evaluate the difference in time to recovery (recovery is defined as seven consecutive low back pain NRS scores of 0–1) between the groups.The effect modification of the allocated treatment strategy by predefined baseline variables (explorative) on low back pain intensity, disability and recovery at 4 and 12 weeks follow-up will be analysed by Cox proportional hazard analyses and logistic regression analyses, respectively. Predefined variables are severe low back pain (defined as NRS ≥ 7) and severe disability (defined as RMDQ ≥ 16) at baseline.To assess the cost-effectiveness of paracetamol versus diclofenac versus advice only for acute low back pain in general practice, a cost-effectiveness analysis will be performed using the primary outcome low back pain severity (measured daily). A cost-utility analysis will be performed to compare our study with other studies in musculoskeletal disorders research in a more general accepted outcome e.g. quality of life ). Utility values of the Dutch public for EuroQol health states will be applied to calculate QALY’s based on the EQ-5D. Using non parametric bootstrapping (randomly drawing 2500 observations with replacement from the patient sample), the degree of uncertainty for costs and health effects and the cost-utility ratio will be depicted in a cost-effectiveness plane. In addition, an acceptability curve will be drawn, which indicates the probability that the paracetamol or diclofenac versus advice only has lower incremental costs per QALY gained than various thresholds for the maximum willingness to pay for an extra QALY.The economic analysis will be based on the societal perspective and on the healthcare perspective in which the direct and productivity costs in the groups will be compared. The costs per hour of productivity loss will be updated from the Dutch Guideline for economic evaluations in health care . The friAll personal data  will be stored anonymously. The patients’ identity will remain confidential at all times. Each patient will be allocated a unique code, which will be used on the Case Report Forms (CRFs). The link between the code and the patients’ name will only be assessed by the researchers and the data-manager.Trial conduct and data integrity will be audited once per year by independent auditors.This paper presents the design for a randomized, placebo controlled trial that will assess the effectiveness of paracetamol, diclofenac and placebo for acute low back pain in primary care. Furthermore, the trial will assess the additional effectiveness of paracetamol, diclofenac and placebo compared to advice only for acute low back pain in primary care. The primary outcome is low back pain intensity measured daily on a numerical rating scale over a period of 4 weeks. Secondary outcomes are measured at 1 weeks, 2 weeks, 4 weeks and 12 weeks of follow-up and include compliance to treatment, disability, perceived recovery, costs, adverse reactions, satisfaction, sleep quality, co-interventions and adequacy of blinding. Between group differences for the primary outcome will be evaluated using a repeated measurements analysis with linear effects models. An economic evaluation will be performed using a cost-effectiveness analysis with low back pain intensity and a cost-utility analysis with quality of life. Explorative analyses will be performed to assess effect modification by predefined variables. The outcomes of this trial may impact the clinical guideline recommendations concerning first analgesic treatment options in acute low back pain in general practice.Recruitment of eligible patients is currently ongoing. Substantial protocol amendments will be communicated to participants, cooperating GPs and pharmacists, Medical Research and Ethics Committee (MREC), the Dutch Trial Registry, ZonMw and the journal publishing this protocol. Results of this trial will be published in a peer-reviewed journal. After publication, participating patients and GPs will be informed about trial results (expected in 2020).