As chronic pain affects 115 million people and costs $600B annually in the US alone, effective noninvasive nonpharmacological remedies are desirable. The purpose of this study was to determine the efficacy and the generalisability of Noxipoint therapy (NT), a novel electrotherapy characterised by site-specific stimulation, intensity-and-submodality-specific settings and a immobilization period, for chronic neck and shoulder pain. Ninety-seven heavily pretreated severe chronic neck/shoulder pain patients were recruited; 34 and 44 patients were randomly allocated to different treatment arms in two patient-and-assessor-blinded, randomised controlled studies. The participants received NT or conventional physical therapy including transcutaneous electrical nerve stimulation (PT-TENS) for three to six 90-minute sessions. In Study One, NT improved chronic pain , function  and quality of life (+88.1%) at follow-up (from 4 weeks to 5 months), whereas PT-TENS resulted in no significant changes in these parameters. Study Two demonstrated similar advantages of NT over PT-TENS and the generalisability of NT. NT-like treatments in a randomised rat study showed a similar reduction in chronic hypersensitivity  compared with sham treatments. NT substantially reduces chronic neck and shoulder pain, restores function, and improves quality of life in a sustained manner. Chronic pain affects 115 million people and costs $600 billion annually in the United States alone, yet effective treatments are lackingTranscutaneous electrical nerve stimulation (TENS) is a commonly used PT treatment modality for pain. Despite the long history of the use of TENS for the treatment of chronic pain conditions, its effectiveness has been inconclusive based on prior randomised controlled trials (RCTs). Multiple studies showed the benefits of TENS345678910111213141517181920622Noxipoint™ therapy (NT), a novel therapy utilising electrical stimulation characterised by precise electrode placement (on “Noxipoints”), intensity- and submodality-specific settings (eliciting soreness/dull pain but not sharp pain) and brief stimulation, was preliminarily found to substantially and persistently restore function and relieve chronic pain in a large cohort of chronic pain patients over the past decade. Two independent RCT studies were conducted. The primary objective of Study One (in the U.S.) was to evaluate the efficacy of NT compared to conventional PT including TENS  for the treatment of chronic neck and shoulder pain based on relative changes in a patient-reported pain scale, functional impairment, and quality of life (QOL) indices from baseline (pre-treatment assessment) to follow-up . The secondary objective was to evaluate the incremental changes in the above outcomes during treatment. The primary objectives of Study Two (in Taiwan) were to verify the findings of Study One using similar outcome measures of chronic neck pain in a geographically different population and to evaluate the generalisability of NT performed by newly trained therapists.In addition, a randomised study in rats was conducted to establish the translational basis for future research on the physiological mechanism of NT. This study examined the effect of NT-like treatment for induced chronic hyperalgesia via intramuscular acid injection2425Thirty-four patients were randomly allocated to different treatment arms in Study One . Although most patients had no clear diagnosis or existing radiological evidence of injury at the beginning of this study, many patients recalled strained muscles, whiplash, pain, etc. associated with these events. Other patients reported gradual degeneration  or a diagnosis of osteoarthritis or could not recall any specific cause of their pain. Study Two focused on chronic neck pain, excluding spondylosis with specific evidence of nerve root compression, implicating muscle or soft tissue impairment.The primary analysis compared the outcomes between baseline and follow-up, and the results demonstrated statistically significant (p < 0.05) and clinically substantial benefits  indicated that the data were marginally normal due to the relatively small sample size in the PT-TENS arm. Most variables associated with the determination of the changes from pre- to post-treatment in the NT group and the differences between the NT vs. PT-TENS arms passed the Shapiro-Wilk normality test (18 of the 20 variables) in Study Two; therefore, a paired t test was appropriate. Nevertheless, Wilcoxon’s tests, nonparametric methods that make no assumptions regarding the distribution of the variables, were conducted in addition to t tests to ensure the robustness of the analysis. All p-values from the Wilcoxon’s tests were in the same range as those from the t tests  and 3.In the first stage of Study One , NT reduIn the second stage, the average BPI “at its worst” in the crossover-to-NT patients was reduced by 84%, from 8.1 at the start of crossover to 1.3  at follow-up . The patients who received PT-TENS maintained pain levels similar to those observed in Stage 1 after follow-up; thus, 7 of the 8 PT-TENS patients crossed over to NT. Alternatively, no patients receiving NT crossed over to PT-TENS because all NT patients reported being pain-free  or nearly pain-free  at follow-up , respectively, and improvements in the functional impairment score by 77.4% and in QOL by 87%. All differences were highly significant . In contrast, PT-TENS patients showed no significant changes in all measures, except a 1.2-point reduction in BPI “right now”. After the PT-TENS patients crossed over to NT (N = 7), they experienced statistically significant improvements in all measures at magnitudes similar to those observed in the NT arm . The difIn Study Two, improvement in all measures was observed at the 4-week follow-up in both NT and PT-TENS patients  were randomly selected for clinical follow-up after 4 to 6 months. Eight of these patients remained pain-free (80%), while the other two (20%) reported minor pain (BPI “at its worst” of 1 and 2 for each patient).Some patients experienced temporary delayed-onset muscle soreness (DOMS), migrating pain, or temporary weakness of the treated area during the treatment period, as explained in the patient’s written consent form and care instructions. No significant side effects were reported.A randomised rat study (N = 18) showed that NT-like therapy significantly (p < 0.01) and substantially reduced (by 80.7%) mechanical hyperalgesia of the hind paw induced by repeated acid injection into the gastrocnemius muscle. This reduction was observed on the second day after the therapy was administered and was sustained until the end of the study (30 days). The control group, which received sham therapy, did not exhibit significant improvement until Day 30, when spontaneous recovery occurred  experienced temporary soreness after TENS in Study One; the soreness typically occurred within a few hours after the electrical stimulation and disappeared within one to three days. This soreness was likely due to DOMS resulting from induced muscle contraction. Many NT patients reported that the pain “moved” from one place to another during or after each application of electrical stimulation. Such pain appeared within a few minutes, hours, or days after the initial pain disappeared. NT was applied to the sources of pain and addressed each source as it emerged. Most patients recalled that the pain from these subsequently appearing sources was pre-existing.A few NT patients with very severe pain or limited range of motion (ROM) at baseline (<15%) reported temporary weakness in the treated area shortly after the pain had been resolved. The muscle typically regained full strength within approximately 3 to 6 days and remained pain-free. No PT-TENS patient reported a similar experience. These possible effects were explained to all patients before and during the treatment. Tissue remodelling may explain this temporary weakness and subsequent recovery.Previously unnoticed pain often became prominent as the initial pain was reduced or eliminated in the NT group. Such “migrating pain” served as both an indicator of the recovery from the initial pain and a navigational cue indicating the next set of impaired muscles/tissues requiring treatment.The reported BPI pain level of each patient reflected the intensity of pain at the most prominent pain sites and was independent of the number of sites treated via NT.It was critical to apply the stimulation to the exact location of the pair of Noxipoints™, which consistently approximated the locations of the origin and the insertion of a muscle group, coinciding with the sites containing the greatest concentration of nociceptors in the muscleStimulation at these paired Noxipoints must induce local soreness/dull pain (matching the characteristic sensation from C-fibres). Other induced sensations  in the absence soreness/dull pain did not lead to positive outcomes after stimulation in approximately 80% of cases.Patient compliance with the instruction to rest was critical in NT. Noncompliance almost always led to a need for repeated NT on the same muscle/tissue. This phenomenon suggests a role of cell remodelling/regeneration in the effects of NT. The estimation of the resting period described in the Intervention section was based on the observed duration of skeletomuscular cell repair mediated by myosatellite cells in the laboratory31NT was conceived and refined over the past decade based on the treatment of over a thousand patients with various types of chronic pain, such as neck, shoulder, back, or knee pain. The key characteristics responsible for the notable advantage of NT over conventional PT, including TENS, include the following.In contrast to the modalities of PT , which were independent and additive, all three elements of NT were found to be indispensable based on thousands of observations during its development. Thus, the objective of this study was to investigate the overall efficacy of NT and to compare it with the collective best practices of conventional PT. We did not intend to analyse individual elements/modalities of any therapy in this study.Neither waveform nor frequency of the electro-stimulation contributed to the difference in efficacy between NT and PT-TENS. Prior studies concluded that different waveforms of TENS did not affect analgesic efficacyDepending on the severity and extensiveness of the pain, various neck (or shoulder) muscles could be involved. In severe cases, the Noxipoints of nearly all muscles in neck and shoulder regions were identified and treated. In milder cases, some patients had been treated at the Noxipoints related to less than ten muscle groups. In this study, muscle groups treated in most patients included trapezius, splenius capitus, rectus capitus, levator scapulae, supraspinatus and deltoid.Often used to characterize the myofascial pain syndrome, Trigger Points  are defined as the tender (hyperirritable) spot in a palpable taut band of skeletal muscle fibersThe microstructure of Noxipoints in each muscle group is assumed to be the receptive endings of nociceptors , which have been observed to be concentrated near the two attachmentsThe proposed mechanism underlying the effects of NT departs from the conventional wisdom about chronic pain at the clinical and physiological levels. Although TENS was used in both the NT and PT-TENS arms, NT was distinct from conventional TENS with respect to its site specificity, submodality specificity and requirement for rest/immobilisation. Only induced soreness/dull pain consistently resulted in pain relief and persistent functional recovery. As the location of NT stimulation had to be at or near the two attachments of the target muscle, which contain the highest concentrations of nociceptorsThe sustained effect of substantial pain reduction and functional restoration in nearly all patients after NT could not be explained by the initial assumption that NT neurologically inhibited pain . The sustained effect, especially in patients with a history of muscle impairment, indicated that the outcome of NT involved muscle/tissue remodelling. The observed requirement for multiple-days of rest of the treated area for full functional recovery suggested the occurrence of cellular regenerationAlthough the exact mechanism underlying its effects is unknown, a neuroimmune signalling pathway from the nociceptive signal to the innate immune cell-mediated repair process may explain the consistent outcome induced by NT stimulation323940Though these two trials and the animal study provided evidence for a promising therapy, longer-term and broader-scope studies of multiple chronic pain conditions are desirable. Further studies of the individual elements of NT are also desirable. Detailed activity monitoring after treatment may be helpful to establish the precise correlation between rest (immobilisation) of the treated area and the effect of NT. Further animal studies would be useful for investigating the mechanism underlying the effect of NT.These studies found that NT substantially reduced pain, restored function, and improved quality of life in a sustained manner in patients with chronic neck and shoulder pain and that NT was superior to conventional PT. Study Two found that the effects of NT are generalisable with respect to different pain levels, ethnicities and therapists.Study One was a parallel, blinded superiority RCT with crossover comparing the effectiveness of NT to that of PT-TENS in patients with chronic neck and shoulder pain. The trial consisted of two stages. The patients in Study One were first stratified based on the Brief Pain InventoryIn the second stage, patients were allowed to cross over to the other arm after completion of treatment in the assigned arm, followed by a washout period (minimum of 4 weeks). At both stages, patient outcomes were evaluated at baseline, at each treatment session, and at follow-up, which was performed approximately 8 weeks after baseline . Note that this crossover design eliminated any potential assignment/selection bias and other known or unknown confounders, which was a key objective of the trial design.Study Two, a parallel, blinded superiority RCT, was conducted to compare the effectiveness of NT to that of PT-TENS for chronic neck pain using the same measures as those used in Study One and following up at 4 and 8 weeks after baseline assessment. The sequence for random allocation to either arm was generated using a computerised random number generator at a 1:1 ratio and was stored by a clerk who was not involved in the trial for concealment. A scheduling administrator, who had no knowledge of the random allocation sequence, assigned a sequential number to each patient who had signed the informed consent form. Each patient was mechanically mapped to the pre-computed allocation sequence by an independent person to avoid assignment bias.All experiments were performed in accordance with relevant guidelines and regulations. Study One was approved by the Alpha Independent Review Board. Study Two was approved by the Research Ethics Committee of National Taiwan University (NTU) Hospital. Both trials were registered in www.clinicaltrials.gov  and conformed to the CONSORT flowchart  and checThe trial design followed the methodology recommended for chronic pain trials2The eligibility criteria of Study One included age of 18 to 64 years, 6-month history of chronic neck pain (ICD-9: 723.1) or shoulder pain (ICD-9: 719.41), at least one prior pain treatment, and BPI “at its worst” ≥5. Neck and shoulder pain were selected because they were often comorbid. The primary exclusion criteria were traumatic bone injury secondary to external forceful impact and pain caused by traumatic bone fractures. The eligibility criteria of Study Two were age of 20 to 70s, 6-month history of neck pain, presence of trigger points, and BPI “at its worst” ≥5. The primary exclusion criteria included cervical spondylosis with imaging evidence of nerve root compression. Detailed patient selection criteria for both studies and the settings and locations in which the data were collected are described in the Patient Selection section of Between 2012 and 2014, in Study One (Study Two), the patients in both arms received three (six) 90-minute treatment sessions within approximately 4 weeks. The patients in the NT arm were treated with electrical stimulation for 90 minutes according to the following guidelines described below. In the pain area, the therapist palpated at or near the attachment points of each muscle group and soft tissue and identified a set of pain points that were sensitive to pressure (termed Noxipoints™). A muscle group or soft tissue was identified as a target when Noxipoints appeared at both of its attachments. Stimulation was precisely applied at the pair of Noxipoints corresponding to the impaired muscle/tissue  for apprδ fibre-elicited sharp pain) and obtaining feedback from the patient before each stimulation. The time required for these activities naturally varied (about 2–4 minutes), as each person was different. The “2–5 minutes” of stimulation in the original protocol was later standardised to 4 minutes per stimulation during NT application. The net outcome of NT was not sensitive to the duration of each stimulation, as the total session time remained the same (approximately 90 minutes). After each treatment session, the patients were instructed not to strain the newly treated muscle or tissue during the “resting period”, which was approximately 3 to 7 days, and to use braces in moderate or severe cases of pain , infrared heat therapy (on the pain site) and ROM exercises  for 15 minutes each in Study One (20 minutes each in Study Two). TENS was applied to general pain areas identified by the patient and reoriented once for 45 minutes in Study One (30 minutes in Study Two). In both studies, the physical therapist was commissioned to optimise the treatment for individual patients within the protocol. In Study One, TENS application was set up as follows: mode, normal; frequency, 10–90 Hz; duration, 200–250 microseconds; waveform, pulsed biphasic, asymmetric square wave; input voltage, 9 V; output voltage: 30–90 V, intensity, maximum tolerable by the patient  up to a maximum available current of 120 mA. In Study Two, TENS application was set up as follows: (a) mode, duration modulation; frequency, 80–100 Hz; duration, 100–150 microseconds; waveform, pulsed biphasic, asymmetric square wave; input voltage, 9 V; output voltage, 30–80 V; and intensity, maximum tolerable by the patient  up to a maximum available current of 120 mA; (b) mode, strength-duration modulation 2 (SD2); frequency, 5–60 Hz; duration, 40–150 microseconds; waveform, variable pulses with automatic increasing intensity and decreasing pulse duration; input voltage, 9 V; output voltage, 30–100 V; intensity, maximum tolerable by the patient up to a maximum available current of 120 mA. TENS application was set at the highest tolerable intensity and frequency based on the patient’s feedback as recommended in prior studiesNo skin preparation was needed for NT or PT in most cases. An electrolyte solution or water was occasionally sprayed on the dry skin or near the hairline to avoid electrical arcing.One licensed physical therapist in each study with a minimum of 12 years of work experience and no knowledge of NT performed the PT-TENS. After the PT-TENS protocol was explained to the physical therapist, he/she was commissioned to optimise outcomes for each patient within the protocol. NT was performed by the original therapist team in Study One and by three newly trained therapists in Study Two. Each new NT therapist was trained via an NT introduction section for four hours by the original therapist followed by approximately 20 practical training sessions (approximately 4–5 patients) before the new therapist began treating patients on her/his own to ensure consistency in locating Noxipoints and performing treatments. The six sessions allocated in Study Two, representing a standard physician’s order for any PT, partially accommodated the inexperience of the NT therapists.The selection of controls was based on multifaceted considerations. Nearly all patients with long-term chronic pain had undergone multiple treatment modalities, including manual therapy, active use of TENS, observation (no treatment), waiting, etc. for years. Although placebo TENS (placing electrodes on sites without applying current) was considered, this treatment was unlikely to pass the sanity check of any patient. Thus, we included TENS with current in the control arm to blind the patient to the treatment. Between TENS with random placement and TENS following conventional PT guidelines, we chose the latter to maximise the effect of the control arm, erring on the conservative side. That is, TENS in the PT-TENS arm was not a sham therapy but rather a component of active treatment.Although little evidence suggested that any specific modality of PT had greater long-term efficacy than placebo, significant evidence showed that most modalities of PT, including placebo, “were almost always better than no treatment in treating chronic pain”The objective of the study was to investigate the overall efficacy of NT and to compare it with the best practice of conventional PT  as an established active comparator. We did not intend to determine which element in NT or modality in PT-TENS contributes more (or less) to treatment efficacy. Thus, multiple modalities of PT with established efficacy were included in PT-TENS as the best-practice active comparator.The primary outcome was the BPI score “at its worst”. The four secondary outcome measures were the BPI scores “average” and “right now”, functional impairment  have been established for chronic pain4546a priori. Investigators who interacted with patients were trained not to compare the differences in expected benefits to avoid a psychological placebo effectTo ensure patient blinding, TENS was included in both arms; the technical difference in TENS application between NT and PT-TENS was not described to the patient The assessment of BPI pain subtypes and interference with functions was blinded, as the patients reported the BPI scores. The assessment of ROM was objectively performed by the provider using a goniometer and was confirmed by the patient in Study One and by a third-party assessor in Study Two.The primary analysis compared all outcome measures at follow-up to baseline for each arm at each stage using t tests and Wilcoxon signed-rank tests. Differences in these outcome measures were further compared using t tests and Wilcoxon rank-sum tests between the NT arm and the PT-TENS arm during the first stage and between the crossover-to-NT and PT-TENS patients during the second stage. Because there were only two time points for the outcome measures in the primary analysis, repeated-measures analyses such as repeated-measures ANOVA were not applicable. All comparisons were tested at the two-sided significance level of 5% . The secondary analysis in Study One further evaluated the incremental changes in these outcome measures during the treatment course. The statistical analysis software R (version 2.15) was used in Study One, and both R and SAS were used in Study Two.All analyses were performed according to the originally assigned arms. Missing data were imputed using last-observation-carried-forward (LOCF). Patients not receiving any post-baseline assessment were excluded. All randomised patients who received any treatment (even only one session) and one post-treatment assessment were included in the analysis to avoid potential bias introduced by excluding dropout patients. The missing outcome measures for these dropout patients  were conservatively imputed using LOCF. Thus, the number of patients analysed was greater than the number of patients observed at follow-up in both studies. All Ns are reported in the CONSORT Flowchart . All patPatients with successful early completion  reported their pain level and QOL by phone; the ROM measures had to be assessed in person and were thus missing for these sessions. These missing interim ROM measures used in the secondary analysis were imputed backward based on the measures observed at follow-up (presumably the worst observation).The effective sample size (before dropout was considered) in Study One was 28 based on the outcome of the preliminary study  in Study Two was 44 based on the outcome of Study One. The plan was to enrol up to 80 patients (with a 1:1 randomisation ratio of the NT arm vs. to the PT-TENS arm). This sample size was expected to provide 90% power to detect a 3-point mean difference between the two arms in BPI “at its worst” from baseline (due to the reduced NT effect expected from newly trained therapists) at a two-sided significance level of 5%, assuming a standard deviation of the change from baseline BPI “at its worst” in both arms of 3 points and a conservative dropout rate of approximately 40% . Note that the actual dropout rate in Study Two was less than expected.The enrolment size of Study Two was larger than that of Study One because (1) the assumed difference of the effect size in the two arms was expected to be smaller in Study Two due to the enrolment of less heavily pretreated patients , (2) the assumption that newly trained NT therapists would be less effective, and (3) the higher expected dropout rate due to the high accessibility of the public healthcare system in Taiwan.Based on the outcome of NT-like treatment in a previous pilot rat study, 18 rats were subjected to induced mechanical hypersensitivity in the hind paw via repeated acidic saline injections  to the gastrocnemius muscle according to standard protocols2449The original study protocols and the full datasets used to produce the results are included as How to cite this article: Koo, C. C. et al. Novel Noxipoint Therapy versus Conventional Physical Therapy for Chronic Neck and Shoulder Pain: Multicentre Randomised Controlled Trials. Sci. Rep.5, 16342; doi: 10.1038/srep16342 (2015).


The relation between chest pain and coronary atherosclerosis (CA) in patients with inflammatory joint diseases (IJD) has not been explored previously. Our aim was to evaluate the associations of the presence of chest pain and the predicted 10-year risk of cardiovascular disease (CVD) by use of several CVD risk algorithms, with CA verified by multidetector computed tomography (MDCT) coronary angiography.Detailed information concerning chest pain and CVD risk factors was obtained in 335 patients with rheumatoid arthritis and ankylosing spondylitis. In addition, 119 of these patients underwent MDCT coronary angiography.n = 50), CA was present in 48.0%. In a logistic regression analysis, chest pain was not associated with CA (dependent variable) (p = 0.43). About 30% (Nagelkerke R2) of CA was explained by any of the CVD risk calculators: Systematic Coronary Risk Evaluation, Framingham Risk Score, or Reynolds Risk Score.Thirty-one percent of the patients (104/335) reported chest pain. Only six patients (1.8%) had atypical angina pectoris (pricking pain at rest). In 69 patients without chest pain, two thirds had CA, while in those who reported chest pain (The presence of chest pain was surprisingly infrequently reported in patients with IJD who were referred for a CVD risk evaluation. However, when present, chest pain was weakly associated with CA, in contrast to the predicted CVD risk by several risk calculators which was highly associated with the presence of CA. These findings suggest that clinicians treating patients with IJD should be alert of coronary atherosclerotic disease also in the absence of chest pain symptoms. Patients with inflammatory joint diseases (IJD) have an increased risk of cardiovascular disease (CVD) –3. DespiAngina pectoris is a symptom of myocardial ischemia caused by coronary atherosclerosis (CA) and may be diagnosed by several techniques. The selective coronary angiography procedure has become the gold standard for diagnosis of CA. This is an invasive, expensive, and resource-demanding procedure. Multidetector computed tomography (MDCT) coronary angiography is another imaging technique for identifying CA . AlthougThe aim of the present report was to characterize and compare the various types of chest pain in patients with RA and AS who were referred for a CVD risk evaluation. Furthermore, we sought to evaluate the associations of the presence of chest pain and the predicted 10-year risk of CVD by use of several CVD risk algorithms, with CA (verified by MDCT coronary angiography).Patients with RA and AS were referred from a rheumatology outpatient clinic or from general practitioners, for CVD risk evaluation at the Preventive Cardio-Rheuma Clinic at Diakonhjemmet Hospital, Oslo, during the period March 2009–July 2012. Details concerning this preventive cardio-rheuma clinic and the approach to identify CVD risk factors, comorbidities, and biomarkers have been described previously . ReferrePatients with RA and AS at moderate to high risk of CVD and/or presence of chest pain were referred to MDCT coronary angiography.This is an observational report from a quality assurance register. Ethical approval and informed patient consent was therefore not required. The data collection/publication has been recommended and approved by the Oslo University Hospitals’ Office of Privacy and Data Protection (2011/7318).The MDCT coronary angiography examination was performed at the Oslo University Hospital, Ullevaal. Two methods were used: first, spiral coronary artery MDCT, where 64 detectors were employed. This method is advantageous when performing reconstruction of the coronary arteries in several planes, including a three-dimensional plane. Furthermore, images of the coronary arteries may be reconstructed during all stages of the electrocardiogram (ECG) cycle. Second, the step and shoot technique was used. This is an ECG-gated MDCT coronary angiography method to reduce movement artifacts during the cardiac contraction cycle. To obtain optimal image quality with minimal movement artifacts, the heart rate should be <60 beats/min. Therefore, the patients were given a beta blocker 2 h before the procedure. The step and shoot MDCT coronary angiography is only performed during certain phases of the heart cycle, which means that the radiation exposure can be reduced by as much as 80% compared to spiral CT. In our center, the step and shoot procedure reduced radiation exposure from 9–14 to 3 mSv. Therefore, the step and shoot MDCT coronary angiography was the preferred method, but when heart rate <60 beats/min was not obtained, spiral MDCT coronary angiography was performed.Iodine-based intravenous contrast medium was used in both MDCT methods, and all patients were asked if they had allergies and, specifically, if they had experienced an allergic reaction against contrast medium previously. Patients with previous allergic reactions to contrast medium were given anti-histamines and/or corticosteroids before the MDCT coronary angiography examination. Contrast medium may affect kidney function. All patients with indication for MDCT coronary angiography in this report had normal kidney function (estimated glomerular filtration rate ≥60 ml/min). Diabetic patients using metformin were asked to abstain from this medication for 48 h after the contrast administration. The kidney function was evaluated after the procedure, and in specific cases, metformin medication was not restarted until the kidney function was normalized.Coronary atherosclerosis was diagnosed by the interventional cardiologist/radiologist. When the quality of the MDCT coronary angiography images was inadequate, or if the examination revealed suspicion of a significant coronary stenosis, selective coronary angiography was performed. In cases of coronary stenosis, individual evaluation was conducted regarding interventions such as percutaneous coronary intervention (PCI), open-heart surgery with coronary artery bypass grafting (CABG), or for optimization of cardioprotective medical treatment.The risk of future CVD was calculated by applying the following CVD risk calculators: (1) the Systematic COronary Risk Evaluation (SCORE) , which pt-test, non-parametric tests, and χ2-tests as appropriate. A logistic regression model was constructed comparing CA versus no CA as the dependent variable in order to assess the associations with both chest pain and CVD risk factors. Instead of investigating the correlation to the CVD risk factors separately, they were examined collectively by applying the aforementioned CVD risk calculators’ estimate of future risk of a CVD event as independent variables in the logistic regression models. Due to the multicollinearity between the CVD risk calculators, separate models were constructed for each of the three CVD risk algorithms. Data analyses were performed using IBM SPSS version 20.The data are presented as crude data, and the results are expressed as mean ± SD and median and interquartile range (IQR) for normally and non-normally distributed characteristics, respectively. The data were compared using independent samples Of the 335 patients with RA and AS referred to the Preventive Cardio-Rheuma Clinic, 104 (31.0%) patients reported chest pain . Disease duration was longer in patients with AS compared to RA patients (p = 0.01). Furthermore, AS patients had more hypertension (p = 0.04) and a higher calculated risk of CVD by use of the SCORE algorithm (p = 0.05) compared to RA patients. On the other hand, RA patients experienced more chest pain than patients with AS (p = 0.04), whereas the proportion of patients with CA was comparable between the two diagnoses (p = 0.48). Associations between CVD risk factors and CA are presented in Table p = 0.001), and had a higher CVD risk evaluated by SCORE, FRS, and RRS  compared to those without CA. In patients without chest pain, two thirds had CA, while in those reporting chest pain, approximately half of the patients had CA , while the calculated CVD risk by SCORE was highly associated with CA (p < 0.001) , whereas chest pain was not . Approximately 30% (Nagelkerke R2) of CA was explained by the calculated CVD risk using all the three CVD risk calculators (data not shown).The characteristics of the 119 patients with RA and AS referred to MDCT coronary angiography is described in Table A Figure . In a lon = 18; 72.0%). Furthermore, indication for selective coronary angiography was found in six patients (24.0%) due to distinct calcification that disrupted the MDCT coronary angiography images and in one patient (4.0%) who had atrial fibrillation. After the selective coronary angiography, approximately two thirds of the patients were in need of optimization of the cardioprotective medical treatment . Indication for further invasive procedures was found in nine patients [PCI n = 5 (20.0%) and CABG n = 4 (16.0%)].Twenty-five patients (21.0%) were referred to selective coronary angiography based on the results of the MDCT coronary angiography Figure . The majThe presence of chest pain is routinely addressed during CVD risk evaluation. The main finding in the present report was that two thirds of the IJD patients without chest pain had CA verified by MDCT coronary angiography, which may be explained by a high prevalence of silent angina pectoris. Chest pain in patients with RA and AS was not associated with CA, but clinicians are advised to ask the patients about the presence of chest pain to reveal those with classical angina pectoris and/or at immediate need of intervention. To our knowledge, the lack of relationship between presence of chest pain and CA in patients with IJD has not previously been reported.In the general population, silent angina pectoris has been reported to occur in 10–15% of patients with coronary heart disease . In the In addition to visualization of CA, coronary artery calcium (CAC) score may be analyzed during the MDCT coronary angiography procedure. The value of CAC score in prediction of CVD events has been thoroughly investigated , 22. NevThere is a preponderance of females with RA, and it is well documented that CVD is diagnosed at later stages in females compared to males . FurtherThe spondyloarthropathies, and in particular the AS disease, comprise inflammation of joints in thorax more commonly than in RA . We therWhen analyzing the various types of chest pain, the number of patients in each symptom group was low, and we were therefore not able to conclude on the importance of the various types of chest pain and their association with CA in patients with IJD.We cannot exclude a selection bias in our cohort in that the referral criteria to the Preventive Cardio-Rheuma Clinic were diagnosed IJD, age between 25 and 85 years, and fulfillment of at least one of the following criteria: known CVD risk factor(s), symptoms/signs of a risk factor, familial premature CVD disease, or simply that a patient wished to undergo CVD risk evaluation. Interestingly, a recent study reported that 30% of RA patients with CVD, diabetes, or hyperlipidemia consulted primary care physicians less than annually, despite frequent visits with other health providers, as rheumatologists . Thus, tIn conclusion, the presence of chest pain was surprisingly infrequently reported in patients with IJD referred for a CVD risk evaluation. However, when chest pain was present, it was weakly associated with CA, in contrast to the predicted CVD risk by several risk calculators, which was highly associated with the presence of CA. These findings suggest that clinicians treating patients with IJD should be alert of coronary atherosclerotic disease also in the absence of chest pain symptoms.All authors have contributed substantially to conception or design of the work; the acquisition, analysis, and interpretation of data; drafting or revising the work critically for important intellectual content; and approval of the final version of the manuscript and agreement to be accountable for all aspects ensuring that questions related accuracy or integrity of any part of the work are appropriately investigated and resolved.Silvia Rollefstad has received speaker honoraria from UCB, MSD, and BMS; Eirik Ikdahl has received speaker honoraria from Pfizer; Jonny Hisdahl has no disclosures; and Tore Kristian Kvien has received fees for speaking and/or consulting from AbbVie, BMS, Celgene, Celltrion, Eli Lilly, Hospira, Merck-Serono, MSD, Orion Pharma, Pfizer, Roche, Sandoz, and UCB and received research funding to Diakonhjemmet Hospital from AbbVie, BMS, MSD, Pfizer, Roche, and UCB. Terje Rolf Pedersen has received speaker’s honoraria and consulting fees from Pfizer and Merck/Schering Plough and speaker honoraria from AstraZeneca. Anne Grete Semb has received speaker’s honoraria form Merck/Schering Plough, AbbVie, BMS, and Wyeth and received speaker’s honoraria and consulting fee from AbbVie and Hoffmann LaRoche/Genentech.


Postoperative pain is a common complication that can lead to serious morbidities and delayed recovery.The aim of this study was to investigate the effect of low-level laser therapy on acute pain after tibial fracture surgery.In this randomized clinical trial, 54 patients who were candidate for tibial fracture surgery were allocated randomly to two groups, namely, control and laser therapy. Both groups had the same type of surgery and technique of spinal anesthesia. Patients in laser group were treated with the combination of two lasers  at the end of the surgery while control group received laser in turn-off mode with the same duration as laser group. Patients were evaluated for pain intensity according to the visual analogue scale (VAS) and the amount of analgesic use during 24 hours after surgery.th, and 24th hours after surgery . In addition, the amount of consumed opioid in laser group was significantly less than the control group .Laser group experienced less pain intensity in comparison with control group at second, fourth, eighth, 12Low Level Laser Therapy is a proper method to reduce postoperative pain because it is painless, safe, and noninvasive and is easily accepted by patients. One of the undesirable complications of surgery is postoperative pain that may result in serious morbidities such as agitation, hypertension, mood changing, tachycardia , 2 and dLow-level laser therapy (LLLT) was pioneered at Russia and Hungry and then at Europe in early 1960s. It is a branch of laser treatments that has been indicated for pain killing and wound healing. LLLT uses irradiation with laser light of low intensity and its effects are not due to producing heat. These nonthermal effects are thought to be mediated by a photochemical reaction that alters cell membrane permeability, leading to increased mRNA synthesis and cell proliferation. FDA has started different investigations on LLLT for 15 years and has approved the use of LLLT for pain relief in carpal tunnel syndrome since 2002 , 12. It Pain following orthopedic surgeries are considered severe pain , 20; henThis double-blind, controlled, randomized clinical trial was conducted in 2012-2013 in Imam Khomeini Hospital, Ahvaz, Iran. The study was approved by the Ethical Committee of Jundishapur University of Medical Sciences (ETH-654) and all subjects signed an informed consent.1-α/2, Z1-β, P1, and P2 at 1.96, 0.84, 0.68, and 0.32, respectively, based on a previous observational study  with 25-gauge needle in the sitting position and with the midline technique.If the systolic blood pressure dropped by 20% or more, 10-mg ephedrine would be injected intravenously. Upon achieving successful anesthesia, pull-tight elasticated tourniquet was clamped and operation was started. The surgical procedures were similar in both groups and included open reamed interlocking intramedullary nailing, which is the preferred approach for treatment of tibial shaft fractures . After the surgery and before the final bandage in surgery room, patients in laser group were treated with a combination of two lasers :2; area, 1 cm2; and time, 20 s/point); andGaALAs hand held probe (PLP-IR) with wavelength of 808 nm and 300-mW output power in continuous mode .GaALInP hand held probe (PLP-R) with wavelength of 650 nm and 100-mW output power in continuous mode, . For radiation on popliteal fossa, the legs were elevated by 60° angels.Each tibial fracture was radiated from four sides in contact technique with the combination of IR and R laser in dose of 9 J/cm2 by the same combination of IR and R lasers .In addition, trigger points on muscles and surgical wounds (6-8 points) were radiated with 4 J/cmFor placebo laser treatment in control group, all those sites were treated with the lasers in turn-off mode with the same duration.th, and 24th hours after the surgery were investigated in both groups. Pain intensity was quantified by visual analogue scale (VAS) in which zero and ten represented analgesia and worst possible perception of pain, respectively. If VAS was three or more, 0.3 mg/kg of pethidine was injected intravenously.One of authors who was blind to the group allocation and did not participate in the laser therapy procedures, filled out the questionnaires. The amount of total analgesic and pain intensity at second, fourth, eighth, 12The data are presented as mean ± standard deviation (SD). We performed Shapiro-Wilk test and Levene's test for normality of the data distribution and equality of variances. Independent samples t test, repeated measure test, and Bonferroni post hoc test were used to analyze the data. P Value of less than 0.05 was considered as statistically significant. All the statistical analyses were done by SPSS software version 16 .Demographic characteristics of participants are presented in th, and 24th hours after surgery in laser group in comparison with the control group. Although there were no significant differences in pain intensity between the second and fourth, the fourth and eighth, the eighth and 12th, as well as the 12th and 24th hours in each group , there were significant differences between the second and eighth, the second and 12th, the second and 24th, the fourth and 12th, the fourth and 24th, as well as the eighth and 24th in each group  used in laser group was significantly less than control group. The mean of total amount of analgesic was 51.62 ± 29.52 and 89.28 ± 35.54 mg in laser and control groups, respectively (P = 0.008).th, and 24th hours after surgery . Similarly, Moore et al. showed that low level gallium-aluminum-arsenide laser for four to six minutes at the end of the cholecystectomy had no significant effect on pain reduction at the first and the fourth hours after surgery; however, the effect was significant at the eighth, 12th, 24th, and 48th hours after surgery . This finding is consistent with the findings of other researchers who reported that LLLT could decrease pain during and after the surgery and had a positive effect on wound healing and edema . LLLT isThe results of this study showed that the combination of laser therapy and analgesic medications had better effect during the 24 hours of recovery after the surgery. Laser radiation at wavelengths of 650 and 808 nm (R and IR laser) can decrease postoperative pain and analgesic use in postoperative period. LLLT does not have side effects like respiratory depression, skin reaction, and analgesic nephropathy that are seen with other methods. It is recommended to perform more studies concerning the applications of LLLT in anesthesia field as it is a noninvasive, safe, and acceptable analgesic method in patients in recovery or surgery room.


Case Study 2on day 1 and capecitabine at approximately 2,000 mg/m2/day (rounded to the nearest 500-mg tablet size) for 14 days on and 7days off (1 cycle = 21 days). A capped body surface area of 2.4 m2 was used, due to the patient’s body habitus.Mr. D., a 55-year-old male, presented to the medical oncology service with a diagnosis of stage III adenocarcinoma of thesigmoid colon. He presented 7 weeks post sigmoid colectomy with lymph node resection and was initiated on adjuvantchemotherapy with CAPOX . Standard dosing was used: oxaliplatin at 130 mg/mAdverse Effects Mr. D. did not report any complications of therapy during cycle 1, days 1–7, other than grade 1 diarrhea, which was amenableto diphenoxylate/atropine when taken. The next week, he reported significant malaise and fatigue associated with persistentdiarrhea occurring every 30 minutes for 5 days. Mr. D. was instructed to go to the emergency room for an immediate evaluation,but he refused.Mr. D. presented to the clinic in poor condition on day 14 of cycle 1. His diarrhea had increased to grade 3 and was notcontrolled with either loperamide or diphenoxylate/atropine, though he was not taking his medications as directed. He had beeninstructed to take two 2-mg loperamide tablets after the first loose stool, followed by 1 tablet of diphenoxylate/atropine 2 hourslater. He could then alternate this with loperamide every 2 hours as needed, not to exceed 8 tablets of loperamide per day. Instead,he had taken 2 tablets of loperamide after the first loose stool, but either waited 6 hours to take 1 tablet of diphenoxylate/atropineor otherwise chose not to alternate the medications at all despite continued diarrhea, depending on the day.Mr. D.’s timing in taking his supportive medications was inconsistent, and his explanations of this timing were not exact. He alsoreported persistent grade 3 nausea with vomiting for 5 days, which did not improve with ondansetron and prochlorperazine,though he again did not take these consistently. He was advised to alternate ondansetron and prochlorperazine every 4 hours asneeded, but only took one or the other medication approximately 3 times per day.According to Mr. D., his adverse effects initially began on day 9 of cycle 1. He had lost approximately 14 kg (31 lb) during cycle1. Clinically, he was found to have grade 2 mucositis and grade 1 hand-foot syndrome. At the time of this visit, his absoluteneutrophil count was 3,000/ìL, his hemoglobin was 14.4 g/dL, his hematocrit 42.2%, and his platelet count was 139,000/ìL. Hiskidney function was within the normal range.Clostridium difficile. He was given IV fluids along with adjustments in supportive medications, including a prescription for 10%tincture of opium. He was instructed to use 0.6 mL every 6 hours in addition to alternating loperamide with diphenoxylate/atropineas noted previously. He was advised to rinse his mouth with a baking soda solution for relief of his grade 1 mucositis, andalternation of antiemetics every 4 hours was reiterated. He was to return prior to initiation of cycle 2 for further evaluation.Mr. D. refused hospitalization despite the primary team’s recommendation. He also refused to undergo stool sampling forWorsening Symptoms The next day, Mr. D.’s wife called the clinic to report that her husband’s diarrhea continued despite the use of tincture of opiumand that it was associated with hematochezia. He was also experiencing a worsening of his mucositis, with an associated swelling ofthe tongue. He was instructed to present to the emergency center, which he did on day 16 of cycle 1. By then, he was found to befebrile at 39.5°C. He was tachycardic, with a heart rate of 126, and he was experiencing significant abdominal pain associated withthe diarrhea. The mucositis was worsening, with new odynophagia.C. difficile. Hisantimicrobial regimen was deescalated to oral vancomycin once his stool volume decreased. He was treated with an institutionalcompounded mouthwash of diphenhydramine, aluminum/magnesium hydroxide, and viscous lidocaine for the mucositis, whichalso slowly improved. He was given a dose of growth factor. Neutropenia eventually resolved, with an absolute neutrophil count of4,820/ìL on the day of discharge. He was discharged 26 days after initiating cycle 1, at which time his myelosuppression andmucositis were also resolved. Throughout his course, he did not report any neurotoxicity.At this time, Mr. D.’s absolute neutrophil count had dropped dramatically to 160/ìL, his hemoglobin was 13.1 g/dL, hishematocrit was 39.2%, and his platelet count was 68,000/ìL. He was admitted to the inpatient service and started on empiricantibiotics. His blood cultures remained negative during hospitalization, but stool cultures were positive for DPD Testing Due to his severe symptoms of neutropenia, mucositis, and diarrhea, Mr. D. was tested for dihydropyrimidine dehydrogenase(DPD) deficiency. Testing confirmed a heterozygous IVS14+IG>A mutation. For this reason, all further adjuvant therapy waswithheld, and he was followed on clinical surveillance only. Fluoropyrimidines such as fluorouracil (5-FU) and capecitabine are commonly prescribed agents for the management ofgastrointestinal, breast, genitourinary, and head and neck cancers, with millions of patients receiving them each year . While these drugs are generally well tolerated at standard doses, studies have shown thatapproximately 31% to 34% of treated cancer patients develop severe, dose-limiting toxicities. This is in part due to the narrowtherapeutic window of 5-FU, combined with high interpatient pharmacokinetic variability, different dosing strategies, and enzymedeficiency . See Table 1 for common grade 3/4 toxicities seen in patients receiving capecitabine and 5-FU.5-FU’s metabolism is a complex multienzymatic pathway. More than 85% of an administered dose is rendered inactivated bythe rate-limiting enzyme DPD, leaving 15% for conversion to active metabolites, which leads to inhibition of DNA synthesis . Capecitabine, an oral 5-FU prodrug, is commonly used in place of 5-FUdue to the convenience of oral administration . It undergoes a three-step enzymaticconversion to 5-FU for its cytotoxic effects. Given that this agent is a prodrug to 5-FU, DPD remains an important component ofcapecitabine elimination.DPYD gene that result incomplete or partial loss of DPD enzyme activity . Partial DPD deficiency is present in approximately 3% to5% of adult cancer patients, with complete deficiency occurring in 0.5% . A deficiency in DPD leads to ashift to active 5-FU metabolites, an increase in the elimination half-life, prolonged exposure, and therefore significant plasmaoverexposure in patients treated with the standard doses of 5-FU . Given the alreadynarrow therapeutic window of 5-FU, DPD deficiency results in exaggerated 5-FU–related toxicities, including neutropenia, mucositis,stomatitis, diarrhea, skin rash, neurologic toxicities, and even death . It has been shown that40% to 50% of patients with grade 3/4 toxicity to 5-FU displayed partial or complete DPD deficiency .DPD deficiency is a pharmacogenetic syndrome caused by molecular defects or mutations in the Literature regarding DPD deficiency in the 5-FU setting is abundant. Less is known about its presentation with capecitabineadministration. It is evident that subtle differences exist between 5-FU and capecitabine with regard to drug interactions and theincidence and severity of common adverse effects . Therefore, it is important to determinewhether differences exist between 5-FU and capecitabine in the presentation of DPD-deficient patients. In the case report at thebeginning of this article, we presented Mr. D., who had a delayed occurrence of capecitabine toxicity and was identified as having aDPD deficiency.DPYD gene and its high number ofpolymorphisms. There are over 40 mutations identified in the gene so far, though many have little or no obvious functional effect;this limits the usefulness of single-mutation genotyping .Given the widespread use of 5-FU and capecitabine for the treatment of GI malignancies, detection of DPD deficiencies withsimple, rapid, and cost-effective screening methods is necessary. Despite the severity of toxicity associated with DPD deficiency,there has been no method for routine screening considered suitable due to technical limitations, wide range of bias, time,availability, and expense . The difficulty lies in the complexity of the The patient in this case was positive for one copy of the DPYD*2A (IVS14+1G>A) mutation, the most frequently detectedmutation associated with DPD deficiency . This is a single-nucleotide polymorphism characterized by a G-to-A mutation in the 5ˇ splicing recognition sequence on intron 14 usually associated with the most severe reported 5-FU toxicities. There are several other deletions, missense mutations,point mutations, and even methylation of the DPYD promoter, which have all been related to DPD deficiency .Select representative DPD deficiency cases within the capecitabine and 5-FU settings are summarized in Table 2. The first case inthe table represents the case of Mr. D. presented here. In addition to our case, one other case of a DPD-deficient patient receivingCAPOX has been reported. However, unlike Mr. D., that patient did not recover from the toxicity. It is interesting to note that thistoxic death case reported after administration of CAPOX was not associated with the most common DPYD*2A mutation, but with aheterozygosity for the 1896C>T mutation also located in exon 14 of the gene .Despite this difference, the two DPD-deficient patients described in the CAPOX cases presented with relative similarity in thatthey both reported initiation of severe toxicities around days 7–9, an atypical delayed reaction based on what has been reportedwith infusional 5-FU . For example,an additional case report involving the use of capecitabine in a DPD-deficient patient indicated that the patient was admitted to theICU on day 11 after initiation of capecitabine .By contrast, a case of DPD deficiency in a metastatic colorectal cancer patient receiving 5-FU with oxaliplatin (FOLFOX) reportedthat the patient developed severe mucositis and odynophagia on day 2 after treatment . He had anIVS14+1G>A homozygous mutation as well as a TA7/7homozygote mutation in the UGT1A1 gene promoter. Another colorectalcancer patient found to be DPD deficient was reported to have developed severe skin toxicities on day 3 after treatment with 5-FUand leucovorin and eventually developed neurotoxicity .All of the previously referenced cases of DPD deficiency appear to have considerably less time to toxicity compared to thosewithout a DPD mutation according to the capecitabine package insert, which reports that the median time to first occurrence ofgrade 2–4 diarrhea is 34 days, and the median time to onset of hand-foot syndrome is 79 days . While there does notappear to be any standard time to toxicity onset for DPD-deficient patients, review of the above-mentioned cases raises thepossibility that the reaction may be delayed for patients taking capecitabine vs. those taking infusional 5-FU.Further, onset and severity in toxicity may differ, dependent on the specific mutation and the degree of mutation. For example,mutations in other alleles can yield similar (if not worse) outcomes than were seen in our case. This suggests that although it is themost common deficiency allele, the canonical IVS14+1G>A mutation might not be a reliable predictive marker on its own . It is also probable that the timing and severity of symptoms are related in part to the heterogeneity or severity ofthe individual polymorphism. All cases suggest that clinical suspicion for DPD deficiency should remain high for patients whodevelop severe toxicities independent of the timing of symptom onset and raise again the question of need for screening prior tostarting a patient on a fluoropyrimidine.DPYD gene can be scanned in 12.5 hours . Currently, these two methods have not been utilized in a standard fashion but may allow expedited determination of DPDdeficiency.While there are numerous methods available to determine DPD status—including mass spectrometry, thin layerchromatography, and the gold standard radioenzymatic assay to name a few—many are expensive, time-consuming, or prone toambiguous results. However, the recent development of a rapid (< 90 minutes), noninvasive, and cost-effective breath test in aclinical laboratory setting may permit the evaluation of DPD activity before the administration of 5-FU . Another approach could be denaturing high-performance liquid chromatography (DHPLC), which canscreen for both known and unknown sequence variations, as the entire If a patient is determined to be positive for DPD deficiency, accepted alternative treatments are sought to avoid any unnecessarytoxicity. In our case, for the patient seeking adjuvant chemotherapy for locally advanced colorectal cancer, the risks and benefits ofadditional 5-FU–based therapy must be discussed with the patient. Due to the severity of Mr. D.’s toxicity, he opted for closeobservation only. Hence, he was strongly urged to be adherent with all future surveillance visits. Because of the likelihood of distantdisease recurrence due to his degree of nodal involvement, we opted to pursue biannual CT scans rather than an annual CT scan. Inthe metastatic colorectal cancer patient for whom chemotherapy is warranted, rather than pursuing 5-FU–based therapy, analternative regimen such as irinotecan plus oxaliplatin (IROX) would be considered ; irinotecan alone as cytotoxicchemotherapy in combination with a biologic targeted agent would be considered as well.Though there is no method of testing that meets the criteria for standardized screening, we suggest that any method of testingis better than "blind administration of standard dosages of 5-FU performed regardless of the DPD status of patients with cancer,"given the countless reports demonstrating the relationship between DPD deficiency and 5-FU/capecitabine-related toxicities anddeath .Advanced practitioners (APs) in oncology who administer 5-FU or capecitabine in any disease state must maintain suspicion forDPD deficiency in patients who develop severe toxicity regardless of symptom timing. It is imperative that APs manage patientsymptoms through aggressive supportive care in hopes of curbing significant adverse effects.


Certain environmental stimuli are frequently reported as typical triggers of migraine pain. Whether these so-called triggers are independent precipitators of migraine pain or mere symptoms of the premonitory phase of migraine remains to be elucidated.In this retrospective cohort study of 1010 migraine patients of a tertiary headache center we assessed the frequency of common trigger factors, premonitory symptoms and accompanying symptoms as well as basic headache characteristics and demographic data.Premonitory symptoms with an onset of 2 or more hours prior to the headache were present in 38.9% of migraine patients, the most frequent being a tense neck, phonophobia and difficulty concentrating. There was a clear overlap of certain trigger factors and the presence of corresponding premonitory symptoms: flickering or bright light as a trigger was associated with higher frequency of photophobia in the premonitory phase. The same applied to the presence of food craving and osmophobia in the premonitory phase and certain foods or odours as trigger factors.Our data thus support the view that commonly reported trigger factors of migraine are not so much independent precipitators of migraine pain, but that they are most likely just misinterpreted results of enhanced attention to certain stimuli mediated by typical premonitory symptoms of migraine pain. Flickering light, bright sunlight, certain odours or certain foods are - among others - frequently reported as typical triggers of migraine pain -11. HoweIn this retrospective cohort study, 1805 patients of a tertiary headache center  upon first admission were presented with a variety of tests and custom questionnaires presented in electronic form between November 2009 and July 2014. During this first admission patients were seen and diagnosed by a trained headache specialist , following the IHS criteria. Patients with a diagnosis of migraine with or without aura were included in the study.As part of the battery of questionnaires, patients were asked for the presence or absence of 27 typical migraine premonitory symptoms . As the amount of missing data sets was low (<1.5%), we did not apply a special correction technique.Data collection in a local data base and use of the data for scientific analysis and publication was approved by the local ethics committee of the chamber of physicians of Hamburg, Germany (submission number PV3185). Informed consent was obtained from all participants. Data were analyzed using SPSS Statistics. Categorical variables were compared using chi-square-test or – in case of cell numbers smaller than 6 – Fisher’s exact test. Continuous variables were analyzed using student’s Of the 1805 headache patients presented with the questionnaires, 1010 patients were diagnosed with migraine. Of these, 699 had migraine without aura and 311 had migraine with aura . Additionally, in patients reporting nausea, photo-, osmo- or phonophobia in the premonitory phase these symptoms were significantly more frequent as accompanying symptoms of migraine pain .In the current study the prevalence rate of premonitory symptoms among migraine patients was 38.5%. We found a huge overlap between certain so-called triggers and the respective corresponding premonitory and accompanying symptoms of migraine pain.There are currently five larger scale studies investigating the frequency of premonitory symptoms in migraine which found percentages between 32.9% and 86.9% of migraine patients reporting premonitory symptoms -20. ThisAs data were assessed retrospectively, a recall-bias might have led to an underestimation of triggers and premonitory symptoms. As however migraine patients have the migraine pain as a recall anchor (e.g. memory aid) and often pay special attention to possible triggers and premonitors, this attribution bias could have resulted in an over-estimation of the described phenomena. Additionally patients of a tertiary headache center are most likely more seriously afflicted by their migraine disorder and the associated symptoms than the general population of migraine sufferers. It is thus possible that the described distribution of symptoms and triggers might not reflect the average of migraine sufferers.Our data show a clear association of the presence of certain symptoms in the premonitory phase of migraine and certain trigger factors corresponding to these symptoms, e.g. photophobia as a premonitory symptom and flickering or bright light as a corresponding trigger factor. The pronounced perception of certain factors as triggers might thus be merely a result of the presence of corresponding symptoms in the premonitory phase of migraine. The presence of e.g. photophobia, osmophobia or food craving might result in a pronounced perception of intense visual stimuli such as bright or flickering light as especially adverse and even pain inducing or in an increased intake of certain foods and thus lead to the conclusion in patients and physicians, that these factors can actually trigger migraine pain. As there is currently no study showing a reliable precipitation of migraine pain by typical trigger factors ,13, it sIt is however also possible that these classic triggers are in fact able to precipitate migraine pain but not independently and at all times: There is currently a lot of evidence that certain parameters of neuronal function  in migraine patients change during different stages of the migraine cycle -25. One Our data further support the assumption that in some patients the typical accompanying symptoms of migraine pain actually precede the pain phase ,17-20,27Our data corroborate the view that most of the reported common trigger factors of migraine are not so much independent triggers that at any time might precipitate an acute attack of migraine pain, but that they are most likely just misunderstood symptoms of the premonitory phase of migraine pain, which is already part of the migraine attack. Future studies investigating “migraine” and also “triggers” have to carefully assess the precise state of the migraine cycle, which must include not only the last but also the beginning of the next attack. We need to characterize the involved neuronal and autonomic subnetworks and their connections during all parts of the migraine cycle if we are ever to understand migraine.


The benefits of an Acute Pain Service (APS) for pain management have been widely reported, but its diffusion is still limited. There are two APS models: anesthesiologist-based and a nurse-based model. Here we describe the development of a different APS model managed by anesthesia residents, and we report the first year of activity in a tertiary Italian university hospital .Patients were included in the APS were those undergoing abdominal and urologic surgery causing moderate or severe postsurgical pain. The service was provided for patients, beginning upon their exit from the operating room, for 4, 12, 24 and 48 h for iv, and up to 72 h for epidural therapy. Vital signs, static/dynamic VAS, presence of nausea/vomiting, sedation level, and Bromage scale in case of epidural catheter, were monitored.P < 0.0001). Patients who underwent to abdominal surgery had a significantly higher self-administration of morphine . Elastomeric pump was the analgesic of choice in half of the urologic patients compared to a quarter of the general surgical patients (P < 0.0001). Among the different surgical techniques, epidural analgesia was used more in open (16.5 %) than in videolaparoscopic (1.9 %) and robotic technique (1.1 %), whereas PCA was predominant in videolaparoscopic (46.5 %) and robotic technique (55.5 %) than in open technique (31.4 %).From September 2013 to April 2015, a total of 1054 patients who underwent major surgery were included in the APS: 542 from abdominal surgery and 512 from urological surgery. PCA and epidural analgesia were more adopted in general surgical patients than in urology (48 % vs 36 % and 15 % vs 2 %, respectively; The creation of APS, managed by anesthesia residents, may represent an alternative between specialist-based and nurse-based models. Perioperative pain can be defined as pain present in surgical patients, caused by a pre-existing disease, the surgical procedure, or by the simultaneous presence of causes correlated with the surgery or pathology . Since tIn a postoperative pain survey, Coluzzi and co-workers showed that postoperative pain continues to be under-managed in Italy: in a sample of 163 Italian hospitals , only 41.7 % had an organized APS, most frequently in university and teaching hospitals . In a seIt is possible to differentiate two main APS models: the first is the US model, which consists of anesthesiologist-based comprehensive pain management teams; the second is a nurse-based supervised APS, more diffused in European countries. Here we present the description of a different APS model and we report the first 12 months of activity.In September 2013, an APS for the post-operative period was organized in a tertiary Italian university hospital . The management of APS was performed by residents of anesthesia.The model adopted was based on residents in anesthesia, the “hub” of the system. Every day, a resident of anesthesia was dedicated exclusively to the APS service from 8 am to 8 pm. During the night, the Intensive Care Unit (ICU) resident on duty carried out the APS, assuring continuity of care. Patients included in APS were those undergoing abdominal and urologic surgery causing moderate or severe postsurgical pain. Operations were classified into major, intermediate, and minor, depending on the degree of pain that might be expected . AccordiThe service included the compilation of special forms for each patient at intervals of time, beginning upon exit from the operating room to 4, 12, 24 and 48 h for intravenous therapy, and up to 72 h for epidural therapy. Vital signs, static and dynamic VAS, presence of nausea/vomiting, sedation level, and Bromage scale in case of epidural catheter, were monitored. For the realization of our APS, we initially used a paper database, stored in a file cabinet. Beginning in January 2015, after modification and optimization of the initial model, a digital database was created, and a laptop  was used to record bedside data. The patients’ records were created directly using a pc in the operating room, and the resident on duty in the APS received data on a laptop through the hospital Wi-Fi connection.Levobupivacaine 0.125 % + fentanyl 0.5 γ/ml, flow of 5 ml/h, patient-controlled bolus of 5 ml with a lock-out of 30 min;Elastomeric infusion pump ;PCA: 0.5 mg/ml of morphine, patient-controlled bolus of 2 ml with a lock-out at 15 min, no continuous infusion;Scheduled iv repeated administration: paracetamol ;Rescue dose (if VAS was greater than 4): ketorolac 30 mg, maximum dose 90 mg/day.The protocol included the following therapies:This retrospective study was approved by the Institutional Ethics Committee of Careggi Hospital, which waived the need of informed consent for data publication due to the retrospective nature of the study and the anonymous data.P < 0.0001); on the contrary, robotic surgery was used more in urologic patients than in general surgery . Duration of surgery was similar among open  and videolaparoscopic, whereas robotic technique resulted significantly longer (P = 0.0080) when compared with the referral technique . On average, general surgical patients also had a significantly higher self-administration of morphine bolus than urologic patients . Elastomeric pump was the analgesic of choice in half of the urologic patients compared to a quarter of the general surgical patients (P < 0.0001). Among the different surgical techniques, epidural analgesia was used more in open (16.5 %) than in videolaparoscopic (1.9 %) and robotic technique (1.1 %), whereas PCA was predominant in videolaparoscopic (46.5 %) and robotic technique (55.5 %) compared to open technique (31.4 %)  in all three surgical techniques. The comparison between static and dynamic VAS in abdominal surgery  is effective but expensive, whereas the nurse-based supervised APS is a low-cost model in terms of the role of the anesthesiologist, which essentially is to teach and train nurses, supervise the APS, and select patients for special pain therapies . Our modLimitations of the present article must be discussed. First, as mentioned above, the lack of historical control group did not permit any comparison in terms of efficacy of analgesic therapy, appropriateness of devices used, complications rate. Second, we were not able to compare different model of APS organization, since this was our first experience. Finally, in consideration of the parameter used in pain evaluation (e.g. VAS), our sample size should be considered limited.The organization of APS should be a primary goal in post-operative care. Our experience suggests that the creation of APS model, managed by anesthesia residents, may represent an alternative between the US one  and the nurse-based model.


The purpose of this prospective multicentric observational study was to confirm the safety and clinical performance of a craniocaudal expandable implant used in combination with high viscosity PMMA bone cement for the treatment of vertebral compression fractures. Thirty-nine VCFs in 32 patients were treated using the SpineJack minimally invasive surgery protocol. Outcome was determined by using the Visual Analogue Scale for measuring pain, the Oswestry Disability Index for scoring functional capacity, and the self-reporting European Quality of Life scores for the quality of life. Safety was evaluated by reporting all adverse events. The occurrence of cement leakages was assessed by either radiographs or CT scan or both. Statistically significant improvements were found regarding pain, function, and quality of life. The global pain score reduction at 1 year was 80.9% compared to the preoperative situation and the result of the Oswestry Disability Index showed a decrease from 65.0% at baseline to 10.5% at 12 months postoperatively. The cement leakage rate was 30.8%. No device- or surgery-related complications were found. This observational study demonstrates promising and persistent results consisting of immediate and sustained pain relief and durable clinical improvement after the procedure and throughout the 1-year follow-up period.  Vertebral compression fractures (VCFs) are well known to cause pain and disability and influence quality of life –3. One oVertebroplasty, first described by Galibert et al. in 1987 , was intThese treatments are efficient in reducing pain and improving quality of life. The ligamentotaxis effect can efficiently reduce the cortical ring using the dynamic mobility of the VCF . KyphoplA variety of new minimally invasive techniques have been introduced as VCF treatment options over the past years. One of these involves an expandable implant  which aims to provide anatomical restoration of the fractured vertebra including cortical ring reduction as well as endplate restoration along with stabilization of the fractured vertebra using a high-viscosity injectable PMMA cement . In biomechanical studies comparing SpineJack with balloon kyphoplasty, Krüger et al. could show the superiority of this new technique concerning height restoration and height maintenance , 17. AddThe primary objective of this first international prospective consecutive multicentre single-arm observational study was to demonstrate the safety and efficacy of this new technique for the treatment of VCF due to osteoporosis and/or trauma.The data included in this report was collected at seven European clinical sites.Between November 2009 and March 2010, 32 patients were included and a total of 39 vertebral compression fractures were treated with the new intravertebral implant system.The patients were given information about the treatment and the follow-up program and signed an informed consent before enrolment. The data was collected at baseline, after 48–72 hours, or at discharge, at 6 and at 12 months. The primary endpoint was to determine the occurrence of cement leakages assessed by X-ray or CT scan. Among the secondary endpoints clinical outcome was measured by reported back pain, quality of life, functional capacity, and the safety of the SpineJack system. Details on patient recruitment and follow-up are given in Detailed information on gender, age, BMI, and fracture classification has been collected and is presented in Complete data was collected from 21 individuals; 2 patients died and 5 did not show up at any of the follow-ups whereas 4 showed up only once, at 3, 6, or 12 months.66.6% of the fractures were located between T11 and L1, 33.4% between L2 and L5. Description of fracture level is provided in All patients underwent a complete physical examination before surgery, including detailed medical history and complete radiographic examination including CT scan to confirm the presence, location, and severity of VCF.A percutaneous transpedicular approach was used for 97.4% of the patients; in 2,6% an open surgery was performed; this patient was treated with a posterior fixation in combination with the SpineJack procedure. The mean duration of the procedure was 38.3 minutes.The SpineJack is an intravertebral body implant intended to reduce vertebral compression fractures. The concept is based on the “in situ fracture reduction” principle where the SpineJack implant is expanded in situ to restore the height and anatomy of the vertebral body mechanically.After restoration high-viscosity polymethylmethacrylate bone cement is injected at low pressure to stabilize the restored vertebra.The SpineJack is implanted using a percutaneous or minimally invasive posterior surgical approach using surgical tools supplied for this system.The 5.0 mm implant is made of titanium alloy (Ti6Al4V). The endplate length is 20 mm and the maximum expansion height is 17 mm. The insertion diameter is 5 mm.SpineJack is inserted into the fractured vertebral body in unexpanded condition, Once SpineJack has reached the desired expansion and the reduction has been achieved, the device is left in place inside the restored vertebra and high-viscosity PMMA bone cement is injected into and around the implant, Outcome was measured using self-completed questionnaires, before surgery, at discharge, and after 6 and 12 months. Pain was assessed by the Visual Analogue Scale (VAS), posture and general self-rated health state by the European Quality of Life score (EQ-5D), and EQ-5D VAS score .Condition specific functional capacity was evaluated by the Oswestry Disability Index (ODI) .Furthermore, the following parameters were recorded by the treating physicians: analgesic intake, duration of hospitalisation, and occurrence of complications. Adverse events (AE) and serious adverse events (SAE) were classified according to the EN ISO 14155 standard during the entire investigation period.Occurrence of cement extravasation was assessed by either X-ray or CT scan or both, Fluoroscopic controls monitored the surgical procedure.Descriptive statistics including quantitative and qualitative parameters were used to describe the number of patients, mean values with standard deviation, median with minimum and maximum values, and percentages of collected data, respectively.t-test for pairwise comparisons was used, depending on the normality of the distribution. P value was defined at 0.001.Within group tests were used to see the time effect, that is, evolution between baseline and follow-up visits. Wilcoxon's test or Student's The rate of cement leakage observed in this study is 30.8%. The leakages were all asymptomatic and had no consequences on clinical outcome. Five leakages (41.7%) were found in paravertebral veins, 4 (33.3%) in soft tissues, and 3 (25.0%) in the intervertebral disc. Half of the leaks were detected only on CT scan.P < 0.001). The results are illustrated in There was statistically significant, immediate, and long lasting reduction in pain as result of the procedure. The overall improvement in pain (VAS), after treatment (48–72 hours), and at 6 and 12 months was statistically significant (n = 31) is −4.6 (2.6), P < 0.001 (Student); the mean improvement between baseline and 12-month follow-up (n = 22) is −6.0 (3.4), P < 0.001 (Wilcoxon). Thus, the pain reduction is more than 3 times the MIC [The mean improvement between baseline and 48–72 hours after procedure  to 10.5% at 12 months postoperatively, which reflects an overall improvement of 83.8%  was statistically significant, of 83.8% .P < 0.001, from 36.2% (at baseline) to 75.6% at 12 months postoperatively, We obtained completed quality of life questionnaires for 30 patients at baseline and 22 patients at 12 months. The results of the EQ-VAS show a statistically significant increase of the quality of life, The mean duration of hospitalisation was 3.7 (SD 2.9) days postoperatively with a minimum stay of 2 days and a maximum stay of 17 days. The long hospital stay for one of the patients was due to a SAE .Two adverse events (AE) (6.25%) were reported, but neither was implant-related. One patient experienced a fracture of the operated vertebral body at 6-month follow-up, and one experienced a collapse of the disc above as a consequence of the trauma.There were 7 serious adverse events (SAE) (21.9%) .None of these were implant- or surgery-related. During this study no device-related complications were reported, and no device had to be removed. There was no surgery-related complication reported during the intervention.This first clinical investigation with one-year follow-up of a new method to treat vertebral compression fractures indicates promising results.High-viscosity PMMA cement was used in combination with the implant in this study. While cement leakage occurred in almost a third of the cases, this leakage rate is still low compared to leakage rates shown in numerous publications on vertebroplasty –23 and sHowever, it should be noted that in this study half of the leaks have been identified after studying CT scans, which is a more sensitive method than assessment by radiographs. Yeom et al.  did showIn this study 22,9% of the fractures were classified as A.3.1 fractures according to the AO Magerl classification. Thaler et al.  recentlyGiannitsios et al.  showed aThe viscosity of bone cement used in the cement augmentation procedure is hypothesized to influence the outcome of the procedure in various ways , 30.The reduction of the VAS pain score, 80,9% at the 1-year follow-up, compares favourably with the findings from a recently published study, comparing results from a new vertebral body augmentation technique compared to balloon kyphoplasty , presentThe cement will interdigitate with the trabecular bone, and thereby it has a potential to stabilize micromovements in the fractured vertebra and relief pain as well as preserve its mechanical strength. Gennari et al. suggest in a publication that not only the stabilization but also the fracture reduction can be of importance for the pain relief .In this study the response to the reduction/stabilization treatment was immediate and persistent during the 1-year follow-up period. All scores in the EQ-5D (including five subscores)  improvedEven more importantly the majority of patients could go back to their normal life demonstrated by significant changes in both EQ-5D and ODI.An important limitation of the study is the observational study design, including lack of a control group, and the limited follow-up period of 1 year.Vertebral compression fractures cause pain and disability and influence quality of life. Therefore, it is our opinion that VCFs should be treated surgically –36. SeveThis clinical investigation has shown promising results regarding safety and efficacy of the SpineJack procedure when used in combination with high-viscosity PMMA bone cement, with statistically significant improvement in all clinical outcomes including pain, functional capacity, patient's quality of life, and decrease in analgesic intake without causing any serious complications. More importantly the majority of patients could go back to their normal life as shown by significant changes in both EQ-5D and ODI. The cement leakage rate is similar to results reported in the literature for kyphoplasty.Randomized clinical trials with suitable controls are needed to confirm these first results.


Quality of life (QoL) is routinely assessed and evaluated in medical research. However, in Japan, there is a lack of solid cutoff criteria for evaluating QoL improvement in chronic noncancer pain management. The present study was conducted to identify the minimal clinically important change (MCIC) of the Japanese version of EuroQol-5D 3L(EQ-5D) utility score and numeric rating scale (NRS) with an emphasis on chronic noncancer pain.The data source for this post hoc research was the post-marketing surveillance (PMS) data for a tramadol/acetaminophen combination tablet, which was previously conducted in real-world settings. The parameters extracted from the PMS data were sociodemographic characteristics, NRS, EQ-5D, and dichotomous physician’s global impression of treatment effectiveness (PGI). The optimal cutoff points of MCIC for EQ-5D utility and NRS scores were evaluated using receiver operating characteristics (ROC) analysis. An anchor-based approach using PGI was applied..16 (0.20) points at 4 weeks from baseline. The changes from baseline in NRS and EQ-5D were significantly correlated . The estimated optimal cutoff points of MCIC for EQ-5D and NRS were 0.10 and −2.0 points, respectively. The area under the curve of ROC was > 0.80 in both analyses.Data of 710 patients with chronic noncancer pain were extracted from the PMS database. The NRS score decreased by 2.7  points, whereas the EQ-5D score increased by 0These results demonstrated novel cutoff criteria for the Japanese version of EQ-5D, focusing on patients with chronic noncancer pain. The obtained criteria were fairly consistent and can be confidently utilized as an evaluation tool in medical research on chronic noncancer pain in Japan, with additional functionality and usability for QoL assessment in pain management practice.UMIN000015901 at umin.ac.jp, UMIN clinical trial registry (UMIN-CTR).The data source of this post hoc research was a PMS study with the identifier number  Of these patients, 55.9 % reported hospital visits due to pain, and 45.2 % of patients who had a hospital visit reported dissatisfaction with the care they received [Chronic noncancer pain is one of the most common harmful experiences worldwide. It is not only responsible for impaired quality of life (QoL) and active daily life but is also associated with high costs because of long medical treatment and loss of work productivity , 2. AmonHealth-related quality of life (HRQOL) instruments, particularly the EuroQol-5D (EQ-5D) , are widAlthough QoL assessment has become common in medical research in Japan, its interpretation still remains unclear. Suka et al. reported that the mean difference of EQ-5D utility scores between patients with low back pain and healthy volunteers was 0.09 in Japanese population , but MCIIn the present study, we conducted a retrospective post hoc analysis to identify the optimal cutoff point (OCP) MCIC of the Japanese version EQ-5D utility score as well as the NRS score and to evaluate the association between the two scores using data from a multicenter post-marketing surveillance (PMS) of a tramadol/acetaminophen combination tablet in patients with chronic noncancer pain.https://www.pmda.go.jp/english/index.html). The PMS was conducted under the Japanese regulation  of good post-marketing study practice (GPSP). All patients registered under the PMS received tramadol/acetaminophen combination tablets for up to 52 weeks based on regulatory approved label information in Japan. In Japan, tramadol/acetaminophen combination is indicated for patients with chronic noncancer pain that is unrelieved by non-opioid analgesic medication. The daily dose was determined at the discretion of each responsible practicing investigator. No restrictions were placed on concomitant medications or physical and psychological therapies.In this study, a post hoc data analysis was conducted using PMS data  collected from 1,316 patients with moderate chronic noncancer pain who were treated with a tramadol/acetaminophen combination tablet (tramadol 37.5 mg and acetaminophen 325 mg per tablet) in routine clinical practice [The sociodemographic data and name of the causal disease of pain were retrieved from PMS data. We also retrieved the NRS  for severity of the pain experienced by patients in the previous 24 h, the Japanese version of EQ-5D 3L  as patiePatient demographics were evaluated using descriptive statistics; categorical data were summarized by frequency and proportion, continuous data were summarized as mean with standard deviation (SD), median, maximum, and minimum.▪ (dNRS in each patient − mean of dNRS)/SD of dNRS▪ (dEQ-5D in each patient − mean of dEQ-5D)/SD of dEQ-5DA linear regression model was applied to evaluate correlation (r) and slope (β) between absolute changes from baseline of EQ-5D (dEQ-5D) and NRS (dNRS). The MCIC of EQ-5D and NRS at Week 4 were evaluated using receiver operating characteristic (ROC) curve anchored by PGI at Week 4. An area under the ROC curve (AUC) > 0.70 was considered as a sufficient level of prediction to identify MCIC . MCIC, tp value < 0.05 was considered statistically significant. All statistical analyses were performed using R version 3.2.1  and JMP 9.0 .A two-sided Data from a total of 710 patients with complete EQ-5D, NRS, and PGI at baseline and Week 4 were retrieved and classified into the post hoc analysis set. Table ± 2.3 points  and 0.16 ± 0.20 points , respectively. Larger mean dNRS was observed in lumbago (−2.9) and osteoarthritis (−2.9), whereas a relatively smaller change was observed in rheumatoid arthritis (−1.7). The largest improvement of EQ-5D was observed in patients with lumbago (0.19), and the smallest improvement was observed in those with rheumatoid arthritis (0.10). The proportion of patients with PGI assessed as “effective” was 86.1 %  at Week 4.Table p < 0.0001). The simple linear regression model indicated that for each 1-point reduction in NRS, the EQ-5D score is expected to improve by 0.045 (m). When stratified by causal disease, none of the groups showed zero slope, but the lumbago, rheumatoid arthritis, and PHN subgroups showed smaller Pearson correlations (r < 0.5).Table The overall MCIC of ROC analysis based on PGI showed a cutoff point of −2.0 points  for dNRS; for dEQ-5D, it was 0.10  Figs. . The spep < 0.001) than the coefficient of EQ-5D .Logistic regression analysis by using standardized dNRS and dEQ-5D as covariates was conducted to further investigate the impact of dNRS and dEQ-5D on PGI judgment. The absolute value of standardized coefficient is compatible between the dNRS and dEQ-5D, and the coefficient of NRS was higher  in Japanese elderly  volunteers [In our study population, the most common cause of pain was musculoskeletal disorders. In a majority of patients, baseline NRS scores corresponding to pain intensity could be qualified as moderate-to-severe pain. While Nawata et al. had reported an average EQ-5D utility score of 0.83  was observed between dNRS and dEQ-5D scores, and both dNRS and dEQ-5D supported the treatment effect of tramadol/acetaminophen therapy. The simple linear regression model indicated that a 1-point reduction in dNRS corresponded to a 0.045-point improvement in dEQ-5D. This conversion ratio may be applicable to clinical practice for chronic pain management when practitioners evaluate clinical outcomes using the NRS or EQ-5D scales. However, there is a possibility that other factors strongly associate with the change of NRS and EQ-5D. For example, an individual patient who had severe side effects would result in a deterioration of QoL. Therefore we need to evaluate QoL and functionality along with pain severity in the treatment of chronic pain patients.In general, pain intensity scores are associated with QOL scale in pain disorders , 20, 21.The primary aim of this study was to estimate the OCP for MCIC of the NRS and the Japanese version of EQ-5D, with an emphasis on noncancer chronic pain using simple and conventional statistical analysis methods. The OCP of MCIC was estimated to be a 0.10-point increase in EQ-5D and a 2.0-point reduction in NRS.Two-thirds of physicians have agreed on an OCP of 2- to 4-point reduction in NRS scores as the MCIC . Salaffip < 0.001) and the EQ-5D utility score (p < 0.001) were independently associated with a more favorable PGI judgment. The absolute value of the standardized coefficient was compatible between dNRS and dEQ-5D, but the coefficient of dNRS was higher (−1.490) than the coefficient of dEQ-5D (0.795), suggesting that physician’s judgment is influenced more by changes in NRS scores than by changes in EQ-5D utility scores. This result was consistent with the result of ROC analysis that the sensitivity of OPC of MCIC on dNRS was higher than dEQ-5D. This may suggest that when judging improvement, physicians should consider improvements in pain severity than improvements in the patient’s QoL.The PGI (effectiveness) and the rate of MCIC achievement of EQ-5D (<0.1) and NRS (< −2.0) were 86.5 % (614/710), 57.0 % (405/710), and 68.6 % (487/710), respectively. The rate of MCIC achievement in both patient-reported outcomes was lower and seemed more conservative than physician’s judgment. A larger discrepancy was observed between physician’s judgment and the ratio of MCIC achievement in EQ-5D than in NRS. In addition, logistic regression analysis using standardized dNRS and dEQ-5D suggested that improvements in both the NRS score (The post treatment changes from baseline in NRS scores and Japanese version of EQ-5D utility scores were well correlated in Japanese patients with chronic noncancer pain. Simple ROC using the PGI-anchored approach estimated a 0.10-point increase as the OCP of MCIC in EQ-5D utility scores and a 2.0-point reduction in NRS scores. Our results demonstrated novel cutoff criteria for the Japanese version of EQ-5D, focusing on patients with chronic noncancer pain. The obtained criteria were fairly consistent and could be utilized as an evaluation tool in medical research on noncancer chronic pain in Japan, providing additional functionality and usability for QoL assessment in pain management practice. The EQ-5D scale is a useful evaluation tool for QoL assessment in real-world treatment of Japanese patients with chronic noncancer pain.Not applicable