With increase of spine surgeries, failed back surgery syndrome (FBSS) prevalence is also rising. While complementary and alternative medicine (CAM) is commonly used for low back pain (LBP), there are no studies reporting use of integrative Korean medicine in FBSS patients.Patients with pain continuing after back surgery or recurring within 1 year and visual analogue scale (VAS) of LBP or leg pain of ≥6  were recruited at 2 hospital sites from November 2011 to September 2014. Weekly sessions of integrative Korean medicine treatment were conducted for 16 weeks  with additional follow-ups at 24 weeks and 1 year. Outcome measures included VAS of LBP and leg pain (primary outcome), Oswestry Disability Index (ODI), Short-Form 36 (SF-36), medical use, and patient global impression of change (PGIC).VAS of LBP and leg pain improved at 6 months . Eighty patients (66.7%) showed improvement of 50% or more in main pain of LBP or leg pain from baseline. Disability and quality of life also improved at 6 months . At 1 year follow-up, conventional medical management use decreased, improvement in pain and disability was maintained, and 79.2% reported improvement of PGIC.Despite limitations as an observational study, integrative Korean medicine treatment showed positive results in pain, function, and quality of life of FBSS patients. Low back pain (LBP) and radiating leg pain have heavier impact on time off work and disability than any other medical condition . AlthougIncidence of FBSS can be roughly inferred from the proportion with unsuccessful outcomes in lumbar surgery-related trials, which is estimated at 4–50%, and incidence in the general population is put at 0.02% in lower estimate and 2% in higher estimation –11. A reIn treatment of FBSS patients, multidisciplinary approaches have been purported to be most effective , and recA considerable portion of patients who found conventional medical management ineffective are turning to complementary and alternative medicine (CAM) treatment for LBP, with one survey stating that 43% of peripheral neuropathy patients use CAM . IntegraHowever, there are no studies on the effect of integrative Korean medicine treatment in FBSS patients, and in light of the fact that many patients are selecting CAM or Korean medicine for LBP treatment, related research is in urgent demand. The authors have previously studied the effect of integrative Korean medicine treatment  for lumbar disc herniation patients in a prospective observational study, and reported the 6 month , 3 year This study is a prospective, multicenter, observational study. Patients with unremitting or recurrent LBP or leg pain after lumbar surgery were recruited at 2 sites of Jaseng Hospital of Korean Medicine  in Korea from November 2011 to September 2014. The majority of participants were not recruited by advertisements but were patients approached upon visiting the hospital for treatment. Jaseng Hospital of Korean Medicine is a spine specialty hospital certified by the Korean Minister of Health and Welfare that pursues an integrative treatment model of conventional and Korean medicine based on conventional diagnostic technology in diagnosis and Korean medicine treatment for the main treatment modality ,24. ThisClinicalTrials.gov Identifier: NCT01701804Patients with LBP or leg pain that did not improve with spine surgery or recurred within 1 yearPatients with current LBP or leg pain with duration of at least 3 weeksPatients with LBP or leg pain of 60mm or higher on visual analogue scale (VAS) scalePatients aged 18 years or older, and 60 years or youngerPatients who are able to take magnetic resonance imaging (MRI) scans and have given consent to taking lumbar MRIsPatients who are capable of free expression of opinion and have given voluntary written informed consent to participatePatients who have agreed to refrain from receiving other pain treatments relating to spinal disorders during the clinical study participation periodPatients with diagnosis of specific serious diseases which are possible causes of spinal pain: e.g. malignant tumors, vertebral fractures, spinal infection, inflammatory spondylitis, cauda equina syndromePatients with progressive neurological deficit or severe concurrent neurologic symptomsPatients with pain from non-spinal causes and/or soft tissue problems: e.g. tumors, fibromyalgia, rheumatoid arthritis, goutPatients with other chronic diseases which could potentially influence interpretation of treatment effect or results: cardiovascular disease, renal disease, diabetic neuropathy, dementia, epilepsyPatients unsuitable for acupuncture, pharmacopuncture or bee venom pharmacopuncture, or at risk of acupuncture-associated safety complications: e.g. patients with hemorrhagic disease (clotting disorders), patients under anticoagulant treatment, severe diabetes patients with risk of infection, serious cardiovascular disease patients, patients with history of severe allergic reaction following bee venom pharmacopuncture or bee stingPatients currently taking corticosteroids, immuno-suppressant drugs, psychiatric medicine, or other medications deemed unsuitable by the researcherPatients in pregnancy or planning pregnancyPatients deemed unsuitable for clinical trial by the researcher upon grounds of diagnostic imaging resultsAll patients received X-ray and MRI tests before study participation, and spine surgery segment and method  were confirmed by radiology specialists and KMDs. However, the definition of spine surgery in this study also included microscopic spine surgeries difficult to discern through radiologic imaging (e.g. discectomy without laminectomy).Integrative Korean medicine treatment was conducted in accordance with patient pain level and state. Treatment frequency was once a week for 16 weeks, and additional treatment sessions were allowed with regard to patient state. Participants were asked to refrain from receiving treatments for LBP or leg pain other than the integrative Korean medicine treatment  or rescue medicine ) stated in the protocol for 16 weeks and discontinued any other LBP/leg pain-related medication. All additional treatment types and frequency was recorded. All interventions were performed by KMDs who had completed 6 years of undergraduate education and 4 years of Korean medicine specialist training courses certified by the Korean Ministry of Health and Welfare.Ostericum koreanum, Eucommia ulmoides, Acanthopanax sessiliflorus, Achyranthes japonica, Psoralea corylifolia, Saposhnikovia divaricata, Cibotium barometz, Lycium chinense, Boschniakia rossica, Cuscuta chinensis, Glycine max, and Atractylodes japonica (120ml). Standard dosage was twice a day.Herbal medicine: Chungpa-jun –28 is anChuna manual therapy : Chuna mAcupuncture treatment: Acupuncture was performed using 0.30X40 mm disposable sterile acupuncture needles . Needles were retained for about 15 minutes per session, and electroacupuncture was applied as needed during retention of needles.Bee venom pharmacopuncture: Sterilized bee venom pharmacopuncture solution was prepared through aseptic processing of 1g of dried bee venom dissolved in 10,000cc of water for pharmacopuncture injection per session applying 0.1cc at acupuncture points using 30-gauge 1cc injection needles to within a total amount of 1cc. Bee venom pharmacopuncture was administered after checking skin test results, and if positive, an alternative pharmacopuncture type was used.The acupuncture points used in acupuncture and bee venom pharmacopuncture were generally selected from 6 common acupuncture points for LBP treatment  and Hyeopcheok points  as standard, and additional acupuncture points conforming to syndrome differentiation following Korean medicine theory were allowed. The total number of acupuncture points for acupuncture and bee venom pharmacopuncture was limited to 10–20 points.NSAIDs were permitted as concomitant medication over the 16 week intervention period in patients whose pain control was insufficient with integrative Korean medicine treatment. Subjects could take up to 3 tablets a day, taking 1 tablet at 8 hour intervals.Primary outcome measures were VAS of LBP and leg pain, which uses a 10cm horizontal line with each end defined as no pain and most severe pain imaginable, respectively, and patients were instructed to mark level of current average pain on the line ,31.Secondary outcome measures included Oswestry Disability Index (ODI) to assess functional status of patients , and theType and frequency of medical use were also assessed. Medication history  regarding LBP and leg pain for the 2 months prior to study enrollment and all treatments other than that specified in the 16 week protocol received during the interventional period were investigated. All forms of medical use were assessed over the follow-up period of 1 year. Adverse events were investigated by assessing causal relationship with current treatment  causality scale)  and seveOutcome assessments of VAS, adverse events, and medical use were performed at baseline, 2, 4, 6, 8, 10, 12, 14, 16, 20, and 24 weeks, ODI and SF-36 at baseline, 4, 8, 12, 16, 20, and 24 weeks, and PGIC face-to-face at 16, and 24 weeks. Blood was drawn for testing at baseline, 8, and 16 weeks and additional follow-up tests were conducted if considered necessary. The 1 year follow-up assessment was conducted by phone and assessed numeric rating scale (NRS), ODI, medical usage, and PGIC.Intention-to-treat (ITT) was performed as primary analysis for all outcomes in all patients (n = 120) who had undergone at least 1 follow-up session, and missing values were handled by last observation carried forward (LOCF). Continuous variables are expressed as mean±standard deviation (SD) and category variables as n (%), and sociodemographic characteristics, history, and medical use (medication and interventions) of study participants were investigated. Each timepoint measurement and baseline of VAS of LBP and VAS of radiating leg pain were compared to assess primary outcome variables, and difference between timepoints (baseline—each timepoint) was analyzed using paired t-test after checking for normal distribution. Analyses were performed for secondary outcome measures ODI and SF-36 in the same manner. The number of participants with decrease of 50% or more in VAS of LBP and leg pain from baseline at each timepoint was also tallied, and the following subgroups were analyzed for trends by timepoint (time by treatment interactions) using repeated measures analysis of variance.Onset of pain post-surgery: Relapse  vs. Continuation (continuous pain persisting after spine surgery)Duration of pain: Pain<6 months vs. Pain≥6 monthsMain site of pain (higher VAS out of LBP and leg pain at baseline): LBP vs. Leg painSex: Men vs. WomenAll statistical analyses used SAS statistical package version 9.1.3 , and significance level was set at p<0.05.The protocol was approved by the Institutional Review Board (IRB) of Jaseng Hospital of Korean Medicine .A total 1,912 patients with history of spine surgery were screened, and the greater majority was excluded from reasons of pain onset, duration or pain level not meeting inclusion criteria. A total 120 patients were enrolled, of which 106 patients (88%) completed the predetermined 16 week integrative Korean medicine treatment program, and 96 patients (80%) attended the 6 month follow-up visit. The 1 year follow-up was conducted by phone in a total 102 patients (85%) out of the initially enrolled 120 patients including drop-out patients .The average age of patients was 41.9±11.7 years, and 72 patients (60%) were male. Ninety-one patients (66.4%) reported pain persisting after lumbar surgery, and the rest were patients whose pain had recurred within a year of surgery after a pain-free period. Average duration of pain was 35.3±53.1 months. Ninety-two patients (77%) had undergone 1 lumbar operation, and surgical history was not evident radiologically in 19 patients . Thirty patients (25%) had received recommendations for re-surgery, and a high proportion of 101 patients (84%) replied that their prior surgery was dissatisfactory regarding satisfaction of previous surgery .In primary outcomes of LBP and leg pain, LBP displayed a mean change of 3.2 (95% CI: 2.7–3.6) at 24 weeks compared to baseline, and that of leg pain was 3.0 . Also, a total 80 patients (66.7%) reported decrease in VAS of 50% or greater at main site of pain compared to baseline (site with more pain at baseline out of LBP and leg pain). Regarding mean change of function and quality of life scores, ODI improved 17.7 points  at 24 weeks compared to baseline, and SF-36 showed a 19.9 point (95% CI: 16.9–22.9) increase .Analysis of medical use type and frequency showed that while 67 patients (55.8%) had taken analgesics during the 2 months prior to enrollment, only a few patients continued to take analgesics after the 16 week period. Also, while 25 patients (20.8%) had received 1 or more ESIs during the 2 month observational period prior to initiation of integrative Korean medicine treatment, few patients underwent ESI after completion of treatment despite the fact that the observational period was longer. Three patients were reoperated on within 1 year of study participation. An average 17 integrative Korean medicine treatment sessions were attended during the interventional period (16 weeks), and most patients received integrative Korean medicine treatment complying to the protocol with the exception of bee venom pharmacopuncture. Bee venom pharmacopuncture was replaced with an alternative pharmacopuncture solution in 57 patients (47.5%) based on skin test results and patient condition. Some participants continued to receive Korean medicine treatment after completion of treatment .Pain and functional improvement was additionally analyzed by major pain characteristics. Between-group difference in VAS and ODI was non-significant in subgroups by onset of pain (relapse vs. continuation), and there were no time by group interactions either. Although between-group difference in VAS of LBP in subgroups of chronic pain (≥6 months) and non-chronic pain (<6 months) patients (p = 0.024) was significant, there were no time by group interactions. Meanwhile, ODI displayed time by group interactions (P<0.001), and patients with <6 months’ pain showed swifter initial functional improvement compared to chronic patients. Patients with main pain of LBP and those with main pain of leg pain showed time by group interactions in VAS of LBP and VAS of leg pain, respectively , and both main pain sites exhibited swifter pain recovery compared to lesser pain sites. Difference by sex was observed in VAS of LBP and ODI results with men showing greater improvement compared to women , but time by group interactions did not exist .The greater proportion of adverse events with potential causal relationships with treatment was gastrointestinal-related. A total 32 patients reported one or more episodes of dyspepsia, diarrhea, or heartburn. Herbal medicine was reduced or temporarily suspended in 3 patients, and symptoms in the other patients subsided or were alleviated despite continuous administration. With the exception of 2 moderate adverse events, only mild adverse events were reported. The 2 moderate adverse events  completely subsided within the follow-up period. Three patients showed mild erythema and urticaria, and all 3 recovered after bee venom pharmacopuncture was administered in reduced amounts and did not show additional allergic reactions.Two patients showed increase of 2 times or over the upper limit of normal range in alanine aminotransferase (ALT), or a combined increase in total bilirubin (TB), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), provided one of them was 2 times or over the upper limit of normal range in blood tests during the interventional period. Both patients were hepatitis B carriers, of which 1 patient was continuously administered herbal medicine without reduction in dosage and blood test results returned to normal at the next follow-up test, implying that there was no causal relationship with herbal medicine. The other patient concomitantly received orthopedic treatment for elbow pain along with herbal medicine after initiation of research, and in addition to repeatedly taking such medicines as chondroitin sodium sulfate, meloxicam, and etizolam, maintained alcohol intake of ≥half-bottle of soju  2–3 times/week resulting in unclear causality of herbal medicine.The lumbar FBSS patients included in our study were chronic pain patients with moderate or higher pain levels, and displayed substantial improvement in LBP and leg pain, disability, and quality of life following 16 weeks of integrative Korean medicine treatment of which pain and disability maintained favorable state at 1 year follow-up. A total 89.4% of participants replied that their current state was improved at 6 months, and 79.2% at 1 year . RecentlThe largest strength of this study is that it is a long-term prospective observation of results of integrative Korean medicine treatment in FBSS patients using various validated measurement instruments. Various effectiveness, safety, and adverse effect evaluation tools were used for comprehensive assessment of patient state. Medical use type and frequency were investigated in detail as observation of change in medical use patterns in these chronic pain patients before and after treatment may be of especial significance. The current treatment protocol closely resembles actual treatment patterns of Korean medicine hospitals in Korea and these study results should be informative to clinicians. The compliance rate for 16 weeks of intensive integrative Korean medicine treatment was high at 88%, and the number of patients presenting with adverse events of moderate or higher level requiring additional interventions was few.There is a distinct paucity of research on Korean medicine treatment or CAM in FBSS patients. This is quite disproportionate considering the abundance of CAM research (e.g. acupuncture) relating to chronic LBP . Two stuThe effect of acupuncture on chronic LBP has been consistently described in previous literature , and theAcanthopanax sessiliflorus, Achyranthes japonica, Saposhnikovia divaricata, Cibotium barometz, Glycine max, and Eucommia ulmoides) and its anti-inflammatory [The main herbal compound of the herbal medicine Chungpa-jun is also known as GCSB-5  using CMM were generally negative compared to this study ,41, whetDespite these limitations, this study is the first long-term study to prospectively observe results of integrative Korean medicine treatment in FBSS patients. In conclusion, integrative Korean medicine treatment produced favorable results in various aspects including pain, function, and quality of life in chronic FBSS patients who generally do not respond well to CMM, and the results were maintained in the long term. However, these observational results of integrative Korean medicine treatment in FBSS patients need further verification through carefully designed RCTs of appropriate samples. Also, whether this method of treatment is cost-effective compared to other surgical or non-surgical treatments is a task left for future studies.


To explore the clinical characteristics of steroid-associated osteonecrosis of the femoral head (ONFH) presenting initially normal magnetic resonance imaging (MRI) results.This retrospective study examined data from 23 cases that suffered from ONFH but presented a normal image at the first MRI examination after corticosteroid therapy from June 2005 to December 2013. Data on protopathy, age, sex, time of pain onset, MRI examination, and initial diagnosis were collected and analyzed.Average time from steroid therapy to first MRI examination was 45.7 ± 25.5 days . Average time to final diagnosis was 199.9 ± 165.8 days . Of the 23 cases, 21 cases complained of discomfort and were misdiagnosed because of a normal initial MRI scan. Twelve hips progressed to collapse and 1 hip received lumbar discectomy when got the final diagnosis. Cases with continuous pain (9/21) presented with pain at a later time than those with intermittent pain (12/21), although the continuous pain cases were diagnosed earlier.MRI performed 2 to 3 months after steroid therapy may present normal images. Another MRI examination is necessary to make a definite diagnosis. Average age of people affected by this intractable disease is quite young, at about 38 years old.Unfortunately, to our knowledge, no studies have focused on the false-negative period of steroid-associated ONFH. Therefore, the purpose of this study was to conduct a retrospective analysis of the clinical characteristics of patients who suffered steroid-associated ONFH in the false-negative period.22.1A retrospective study was conducted with a cohort of 23 patients who had received steroid therapy for different reasons and were confirmed to have ONFH, but presented normal results at their initial MRI examinations. The study took place from June 2005 to December 2013. The ethics committee of our hospital approved the study protocol, and all patients provided written informed consent. Mean age of subjects was 33.2 ± 10.1 years . There were 11 men and 12 women. Fifteen patients suffered bilateral ONFH and 8 suffered unilateral ONFH. Corticosteroid dosages ranged from 367 to 7544 mg, and the median dosage was 2150 mg . Of the 23 patients in the study, 21 underwent initial MRI examinations because they felt discomfort. The other 2 patients received their initial MRI examinations for osteonecrosis screening.2.2 were collected. Patients were asked about their pain status (continuous or intermittent) at each of the 2 MRI examinations.Data on protopathy, types of corticosteroids taken, dosage of corticosteroids taken , time of pain onset, location of initial pain, time of initial MRI, time of final diagnosis, and stage 2.3Two MRI protocols  were conducted on 2 machines: aSigna Excite 1.5-T Imager  and a Philips 1.5-T Imager . With the Signa machine, coronal T1-weighted sequences (repetition time [TR] 400/echo time [TE] 8.6/Ef) were obtained using a pelvic phased array coil and coronal STIR images were obtained using a TR of 2560 ms and a TE of 108 ms. Images (4-mm thick with 1-mm gaps and a 34 × 34-cm field of view) were obtained using a 256 × 192 matrix with the number of excitations (NEX) set to 4. With the Philips machine, coronal STIR images  and coronal T1-weighted sequences (TR 340/TE 15) were obtained with a 5-mm thickness with 2-mm gaps. A low signal band on the T1-weighted image and a high signal band on the corresponding STIR sequence were deemed as the MRI diagnostic criteria of ONFH.2.4t test. The chi-squared test was used to analyze relationships between sex, pain status, pain location, and steroid type. A P-value <.05 was considered significant.Data analysis was carried out in SPSS software . Age of patients, time of pain onset, time of first MRI examination, time of final diagnosis, and steroid dosage were analyzed by using Student 3Clinical data for 23 patients, including protopathy, corticosteroid type, corticosteroid dosage, time of pain onset, location of initial pain, time of initial MRI, and time of final diagnosis, are summarized in Table In this study, 21/23 patients complained of discomfort after receiving steroid therapy but presented normal results at their first MRI examinations. Two patients did not experience any pain and underwent their first MRI examinations to screen for ONFH. Of the 21 patients who complained of discomfort, the average time from steroid administration to pain onset was 30.7 ± 24.4 days , to the first MRI examination was 45.5 ± 26.6 days , and to final diagnosis was 199.7 ± 173.6 days . Time intervals were similar for male and female patients  patients (32/72) by MRI approximately 3.1 months after high-dose glucocorticoid treatment. Similarly, Saito et al found that 48/286 patients presented with MRI evidence of ONFH within 12 months of initiation of steroid therapy following kidney transplantation. In addition, 29/34 patients showed a low-intensity band on T1-weighted images 6 to 12 weeks after renal transplantation, and 35/38 patients showed band patterns 24 weeks after renal transplantation, but none of these patients showed abnormal results 4 weeks after kidney transplantation.Corticosteroid use is a leading cause of ONFH. For ONFH patients requiring continuous steroid use for treatment of background diseases, no expansion of the necrotic lesion was found. In a prospective study of 291 joints in 106 SLE patients without osteonecrosis after initial steroid therapy, only 6 joints developed new osteonecrosis, which only occurred after SLE recurrence in association with increased steroid doses. New lesions were delayed for a mean of 5.9 years after initial steroid administration. Mean time from SLE recurrence to appearance of new lesions was 6.2 months.Among 539 patients who received steroid therapy for SARS infection, osteonecrosis was detected within 6 months after steroid administration. All patients were rescreened by MRI 4 years later, which revealed no new lesions.Our results are consistent with those of previous studies. In this study, average time between steroid administration and initial MRI scan was 45.7 ± 25.5 days  and between steroid administration and ONFH diagnosis was 199.9 ± 165.8 days . All of these studies indicated that the adverse effects of steroid-induced osteonecrosis are time limited. Onset of ONFH might be assumed to occur 0 to 6 months after steroid use, with presentation on MRI 1 to 6 months after steroid therapy.,3,11 Most asymptomatic ONFH cases will develop to symptomatic ONFH within 5 years. Untreated ONFH has a poor outcome and often leads to subchondral collapse within a short period.,21 Surgical head-preserving procedures are helpful to relieve pain and improve function of the affected femoral heads only in the early stage.–9 Most patients must undergo total hip arthroplasty when the femoral head collapsed. Even with great progress in the design and technology of prostheses, revision (with unfavorable prognosis) is needed 20 to 30 years later.,23 Thus, early diagnosis is very important for a good prognosis. Knowledge of the time lag between steroid use and MRI-detectable disease can aid us in making a detailed and reasonable screening plan. In this study, 21 cases with discomfort were misdiagnosed because the initial MRI presentation was normal. Twelve hips progressed to the collapsed stage, and 1 received lumbar discectomy after the final diagnosis. All of these events could be avoided if another MRI were performed 6 to 12 months after steroid therapy.ONFH is an intractable disease that affects relatively young, active patients, with a mean age of 36 to 38 years.,25 Other methods, such as electromagnetic stimulation, extracorporeal shock-wave therapy, hyperbaric oxygen, and core decompression, may alter the prognosis of ONFH.–9Characteristic presentation of ONFH is a low signal band on T1-weighted image and a high signal band on the corresponding STIR sequence. The latter corresponds to the development and calcification of vascular connective tissue between healthy and necrotic bone. Although granulation tissue development is a physiological response that contains the lesion and promotes healing, the subsequently formed fibrosis and sclerotic bone act as a barrier to revascularization of the bone marrow and the transport of the cytokines and other cellular mediators needed to remodel the bone. Necrotic bone has poor biomechanical properties. When mechanical constraints exceed bone resistance, stress fracture occurs, resulting in femoral head collapse and hip osteoarthritis. The use of some drugs, such as lipid-lowering drugs, anticoagulants, vasodilators, and traditional Chinese medicines, during the time lag period may reduce occurrence of necrosis.,27 reported that some patients experienced pain, mostly involving the hip and knee joints, early after treatment with steroids. In general, this “fleeting joint pain” is severe, lasts up to a week, and is accompanied by negative imaging results. Fleeting joint pain may resolve by itself or be treated with calcium antagonists. The mechanism of fleeting joint pain has yet to be elucidated but may be related to corticosteroid impulse therapy. In this study, 12/21 patients complained of short-term pain 4 to 30 days (average 14.7 ± 8.3 days) after steroid therapy. Another MRI was performed when the pain recurred. These patients met the criteria of fleeting joint pain syndrome. The remaining 9 patients complained of pain later, 52.0 ± 22.3 days after steroid therapy. This pain persisted until osteonecrosis was confirmed by a second MRI examination.Previous studiesCase 6 complained of right hip pain 48 days after steroid administration for idiopathic deafness. X-ray and MRI performed 2 days later were normal Figs.  and 2. TThere are several limitations in this study. Firstly, the number of cases in this research was small. We only collected 23 cases from June 2005 to December 2013. One reason for this small sample size was that most cases of early-stage ONFH were painless. Another reason was that MRI was not performed in a timely manner when patients complained of discomfort. Secondly, the nature of this study was retrospective, and MRI was performed irregularly. Large-scale prospective studies are required to study the false-negative phase of MRI after taking corticosteroids and to investigate the relationship between dosage of steroid and the presence of ONFH on MRI.


The Control Group (CG) received only the standard hospital treatment. Participants were evaluated at the beginning of the study to establish a baseline and reevaluated at the end of 12 weeks.p = 0.0047), pain intensity (p = 0.0082), and the extent to which pain interfered with their daily life (p = 0.0047). There was an increase in maximum oxygen uptake (p = 0.0001), flexibility (p = 0.0001), and strength on both sides (right p = 0.0001 and left p = 0.0008). No significant differences were observed in fatigue (p = 0.0953) or BMI (p = 0.6088).Patients in the SG showed a significant decrease in total pain points (2 max, flexibility and static strength in patients with breast cancer.Combined training was effective in decreasing pain and increasing VONCT03061773. Registered on February 19, 2017, ‘retrospectively registered’. Cancer accounts for more than 8 million deaths worldwide. It is estimated that the number of new cases will increase by 70% over the next two decades, making cancer one of the principal causes of morbidity and mortality. Approximately 60% of the new cases of cancer occur each year in Africa, Asia, Central and South America; these regions are also responsible for the majority of cancer deaths . EstimatTreatment for breast cancer is expensive: it costs more than $ 13.89 for a single patient to undergo biopsies, sectorectomy, chemotherapy (taxanes followed by anthracycline), radiation therapy, and 5 years of tamoxifen. These costs can be even higher depending on the treatment regimen, making breast cancer a public health problem .The adverse side effects of cancer treatment include pain, fatigue, cachexia (wasting syndrome), diminished strength and lung capacity, and reduced range of movement, among others , 21, 29.Pain is one of the most common symptoms in patients with breast cancer, with 30–60% experiencing moderate to intense pain . In addiPain tends to decrease by physical training, which increases strength, cardiorespiratory fitness, flexibility, and quality of life, and decreases fatigue, length of hospital stay, anxiety, depression, stress, sleep disorders, nausea, and vomiting. It also contributes to better responses to treatment, body image, mood, and body mass maintenance (maintaining or increasing muscle tissue and reducing body fat) , 19, 23.In a multi-centric study with 301 patients undergoing chemotherapy, it was observed that higher-intensity aerobic training was more effective at decreasing pain, compared to lower-intensity aerobic training and combined training. However, pain assessment in the previous study was performed by using a quality-of-life questionnaire rather than using a specific scale .Combined training has been studied as a means for decreasing pain in patients with breast cancer. One study demonstrated that combined training, which included aerobic and resistance exercises for eight months, succeeded in decreasing pain . Another2 max), body mass index (BMI), flexibility, and strength in patients with breast cancer.The present study aims to evaluate the influence of a 12-week course of combined training containing aerobic, resistance, and flexibility exercises on pain, fatigue, maximum oxygen uptake  or being observed due to breast cancer at the Aldenora Bello Cancer Hospital (HCAB). This study excluded patients with mental or psychological disorders, those who were incapable of verbal communication or physical movement, and those who were pregnant or breastfeeding. Patients were excluded from the study if they missed three consecutive sessions, did not complete the evaluations, experienced psychological disturbances, became pregnant, quit, died, or were removed from the study by doctor’s orders.Participants were informed about the objectives of the study and written informed consent was obtained. The study received approval from the Committee on Ethics in Research of the Federal University of Maranhão (UFMA), under protocol 20665713.2.0000.5087.Anthropometric measurements, such as weight (kg), height (cm) and age (years), were taken .The marital status , educational level , employment status , and family income  were ascertained by history-taking. Several hemodynamic variables were considered, such as the resting heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) following resting in a comfortable position for 5 mins .The type of tumor, pathologic stage of cancer  , the phaThe level of physical activity was assessed using the short version of the International Physical Activity Questionnaire (IPAQ). The participants were classified into the following: very active, active, occasionally active, and sedentary  . Each paThe pain was assessed using the Brief Pain Inventory (Attachment A), validated for Brazilian Portuguese. This research tool evaluates not only the intensity and location of pain but also the degree to which pain interferes with a patient’s daily life and the effectiveness of pain management therapies; thus, the use of scales in hospital assessments can make it easier to identify and treat pain .The questionnaire’s cut-off points are 4 for moderate pain and 8 for severe pain . Each score in the inventory varies from 0 (no interference or no pain) to 10 (the worst possible pain). The inventory is evaluated by looking at the numerical scores for each question; in other words, there is no general overall score for the questionnaire. In evaluating the dimensions, scores for each question in the inventory were averaged [FatigueFatigue was assessed using the Revised Piper Fatigue Scale (PFS-R), a validated instrument made up of 22 items distributed in three dimensions: behavioral, affective, and sensorial-psychological or sensorial-cognitive-emotional. Fatigue was then measured by averaging these three dimensions .2 max)Maximum oxygen uptake (VO2 max was determined using the American College of Sports Medicine (ACSM) submaximal cycle ergometer test [VO2max (ml− 1Kg− 1)* = 9.39 (measured in Watts) + 7.7 (body weight in kg) – 5.88 (age in years) + 136.7. * VO2max (ml− 1Kg− 1 min− 1) = Divided by Kg. Estimated standard error = 147 ml/min.The volume of VOBody mass index (BMI)2 [The BMI was obtained from the height and body mass using the formula BMI = mass (Kg) / height (m) FlexibilityFlexibility was measured using the sit and reach test, which measures the flexibility of the hip joint as well as the lower back and hamstring muscles. The test used a Wells bench (Wells Portable Instant Pro Sanny) attached to a wall, where patients supported their feet, approximately at the width of their hips. With clasped hands, the patient stretches, reaching towards the bench as far as they can, without bending their knees or feeling pain. The furthest stretch out of three attempts was recorded as the measure of their flexibility .StrengthStatic strength was measured through the grip strength test, using a hand dynamometer (Jamar Sammons Preston), which has a scale from 0 to 100 k. Patients took the test by squeezing the dynamometer as tightly as they could without bending their elbow or altering their posture, in three repetitions, alternating their hands .The combined training program consisted of a 12-week long course of aerobic, resistance, and flexibility exercises, with three sessions per week devoted to aerobic and resistance training in the same session , and two sessions per week devoted to flexibility training (without supervision). The aerobic/resistance and stretching sessions took place on alternate days.FamiliarizationParticipants were familiarized with the stretching exercises for 2 weeks, in three sessions per week, during this period each patient was coached on the correct performance of the stretching exercises. Familiarization with the aerobic and resistance training took place in three sessions over the course of a week, during which the cycle ergometer (stationary exercise bicycle) regimen was with 15 watts, and the resistance training regimen was with the patients’ body weight and a light Theraband, with 8–12 repetitions at one-minute intervals for each exercise.AerobicsTHR = x. (MHR – RHR) + RHR, where x: % of the target effort, MHR: maximum heart rate, and RHR: resting heart rate. MHR was obtained using the cardiorespiratory test, and RHR was measured with the patient at rest. The THR was measured using a fitness monitor (Polar FT2).Aerobic training was regulated using the target heart rate (THR)  from theThe cardiorespiratory fitness test was carried out using the ramp protocol  on a cycThe rating of perceived exertion (RPE) was used to verify the intensity of individualized training , with patients verbally encouraged to reach their highest possible level of fatigue.ResistanceThe protocol for resistance training was three series of 12 repetitions for each exercise, with one-minute intervals between repetitions and series. Each movement was conducted at a speed of 3 s for the concentric phase and 3 s for the eccentric phase . The exeThe training weight was determined by having the patient do 12 repetitions 72 h after familiarization . PatientFlexibilityThe flexibility training involved active stretching (greater range of movement by a joint by contracting the agonist muscles and relaxing the antagonist muscles) without pain, where each exercise lasted for 20 s in three series . The strWeight progressionWeight progressions were carried out every 4 weeks, respecting each patient’s individual biology in the cardiorespiratory fitness test and the maximum repetitions for predicting the initial weight . AerobicEach session of aerobic and resistance training lasted 60 mins, in the following order: 30 mins on the cycle ergometer (stationary exercise bicycle), hip flexion and extensions, shoulder exercises, squatting with a Swiss ball , French presses (triceps extension exercises), and lifting exercises for the dorsal muscles. The flexibility training session lasted approximately 15 mins.The sample was for the convenience of breast cancer patients, and they were randomly assigned to intervention groups. Thirty-one patients participated in the research project, divided into a study group (SG) and a control group (CG).The sample of the pilot study was used for a sample inference of a controlled clinical trial in the Stata 10.0 program, using a test power of 80, 5% alpha, 1:1 division of groups in a matched pair test. The average pain of patients in the SG before the combined training (CT) was 4.79 ± 2.99; after the CT, it was 2.79 ± 2.22, yielding the results for a new study of 56 patients .Patients were contacted and invited to participate in this study by telephone, through invitations issued at regularly-scheduled meetings with HCAB patients, and by referral from oncologists, mastologists, physiatrists, physical therapists, psychologists and pain management specialists. Patients who showed interest received a complete explanation of the study.SG, which underwent combined training (CT) for 12 weeks in addition to continuing their conventional hospital treatment (CHT) to breast cancer .CG, which underwent only CHT for 12 weeks and did not perform any physical training.Groups were divided 1:1, with one additional patient in the CG. The groups were:Assessments of both the SG and the CG were conducted at the study’s outset to establish a baseline, and at the end of 12 weeks, corresponding to the length of the combined training intervention. The team was trained in the application of each survey and test procedure, and the researchers were blinded with regards to the physical assessments, only being informed of the day and time of the assessments.2 max, BMI, flexibility, and static strength.The Kolmogorov-Smirnov test was used to verify the normality of the variables. Variables were found to be normal for age, height, weight, HR, resting SBP and DBP, total points on the pain scale, the factor of pain intensity with regards to more, less, average and current pain, the factor of pain’s interference in the patient’s general activity, work, relationships, sleep, enjoyment of life, fatigue, VOThe matched pair student t-test was applied to the dependent and parametric variables, while the Wilcoxon matched pair test was applied to non-parametric and ordinal variables, and McNemar’s test was applied to paired and dichotomous variables. F test was used on independent parametric variables, and since all showed similar variations among the groups, the non-matched student t-test was applied. The Mann-Whitney test was used on independent non-parametric and ordinal variables, and the chi-squared test was applied to independent and dichotomous variables.r = 0.2–0.4), moderate (r = 0.4–0.6), strong (r = 0.6–0.8), and very strong (r= > 0.80) [p < 0.05 considered as statistically significant.The secondary outcomes showed normal correlation with the pain intensity. The Pearson correlation test was used, with classifications being negligible (r = < 0.2), weak ( > 0.80) . The staOut of the 300 patients contacted, only 31 were willing to participate in the study. Of these, one patient had to be excluded from SG because of a diagnosis of mental disorder; in CG, one patient died, and another one failed to complete the final assessment. Overall, 28 patients completed the study  , marital status , educational level , employed , household income , hemodynamics , type of tumor , stage of illness , phase of treatment and observation , time since diagnosis , level of physical activity  and time since most recent physical training . This shows homogeneity among the groups , measurements of pain intensity  and the degree in which pain interfered in the patient’s life . Similar measurements in CG remained the same. There were no significant differences among the groups at the outset of the study or after 12 weeks , flexibility , and static strength  in both hands of participants in SG increased significantly, in contrast to those in CG. VO2 max also displayed a significant difference between the groups at the base . However, the difference was even greater after 12 weeks . However, fatigue  and BMI  were not significantly decreased in the SG  and after 12 weeks , differently than the volume of maximum oxygen uptake, body mass index, flexibility, and static strength on the right and left sides for SG. Fatigue was also significantly correlated to pain intensity in CG  (Table Pain intensity showed a strong positive correlation with fatigue in SG at both the baseline measurement (There is no consensus in the literature regarding the ideal management of pain in patients with breast cancer; clinical studies that assess pain as an outcome in these patients are scarce , 6. In tThe combination of three types of different training in the present study may have contributed to the reduced pain in our group of patients with breast cancer. Aerobic exercises raise the peripheral levels of beta-endorphins, which reduces the sympathetic system activity, increases sleepiness, and produces psychological stability, in addition to improving the serotonergic system and the relation between nerve endings and the size of muscle fibers. Resistance exercises produce better synchronization of motor unit firings, more efficient motor unit recruitment, central nervous system activity, and motor-neuron excitability, in addition to depressing the inhibitory neural reflexes and inhibiting Golgi tendon organs , 35. Fin2 max, flexibility, and strength. This demonstrates that physical training can be an effective non-pharmacological intervention during and after treatment for breast cancer.In addition to reducing pain, the exercises in this study also increased VOOne study showed an increase in cardiorespiratory fitness achieved through a 12-week aerobic training program . This di2 max with combined training may be due to the increase in cardiac output, and more significant interaction between alveolar ventilation and capillary blood flow, as well as skeletal muscles’ higher oxidative capacities, brought about by the exercises. The very low baseline readings for VO2 max among patients who did not participate in the combined exercise training group after 12 weeks is considered severe, since ventilation efficiency indices are adversely affected when VO2 max is less than 20 ml.kg− 1.min− 1, which is often the case for patients with severe cardiac insufficiency. Low VO2 max may be due to the toxicity caused by chemotherapy and radiation therapy, where hypoactivity in the parasympathetic system and hyperactivity in the sympathetic system activate the network of proinflammatory cytokines, which are present at high levels in patients with fatigue and cancer [The increase in VOd cancer , 31.The process of cachexia and sometimes weight gain may explain the inverse correlations between reduced flexibility and strength, and increased pain in patients who did not engage in physical training , 33.No difference in BMI was observed among patients in this study, which corroborates the literature, such as a study that compared aerobic training with higher-intensity aerobic training and combined aerobic-and-resistance training , as wellCancer patients can change their metabolism such as degradation of muscle mass, reduction in functional capacity, and loss of body fat. However, cancer treatment itself can cause the opposite, i.e., weight gain. Weight gain is also a function of aging; middle-aged women gain weight at the rate of 0.5 kg per year , 33. TheAlthough the proposed protocol did not reduce fatigue, this last one showed a significant positive correlation with pain intensity, both at the study’s outset and after 12 weeks for both groups. This symptom stems from some causes, such as psychological, social cognitive, behavioral and physical factors, as well side effects of radiation therapy, chemotherapy, and medications such as letrozole and exemestane used in hormone therapy , 30.2 max and the small sample size. However, research projects focusing on patients during and after cancer treatment encounter difficulties with sample size because of adverse treatment effects and financial circumstances; this may contribute towards difficulty in patients getting to the locations where the physical training was offered [This study’s limitations include the indirect assessment of VO offered . The hom offered .2 max, flexibility, and strength in patients with breast cancer. One of this study’s strong points was the use of combined training that—unlike other studies—included a 12-week course of aerobic, resistance, and flexibility exercises in five sessions per week; another strong point was the choice of pain management as a principal outcome, using a specific pain scale for cancer patients.Nevertheless, with this small sample, we found that combined training was able to reduce pain and increase VOThis study demonstrated that combined training reduced total pain points, pain intensity, and interference of pain in patients’ daily lives, as well as increased maximum oxygen uptake, flexibility, and strength. However, no significant improvement was observed in fatigue or BMI for patients with breast cancers. Combined training that includes aerobic, resistance and flexibility exercises can be a useful aid to pain management for patients undergoing breast cancer treatment. Future research will be required to test the results observed here more efficiently.


Acute periradicular abscess is a condition characterized by the formation and propagation of pus in the periapical tissues and generally associated with debilitating pain.The aim of this study was to compare the overall analgesic effectiveness of two combinations of opioid and non-opioid analgesics for acute periradicular abscess.This study included 26 patients who sought emergency care in a Brazilian dental school. The patients were randomly divided into two groups: Co/Ac - oral prescription of codeine (30 mg) plus acetaminophen (500 mg), every 4 h, for 3 days or Tr/Ac - oral prescription of tramadol hydrochloride (37.5 mg) plus acetaminophen (500 mg) on the same schedule. Two factors were evaluated: (1) pain scores recorded by the patients in a pain diary 6, 12, 24, 48, and 72 h after treatment, using the Visual Analogue Scale; and (2) the occurrence of adverse effects.In both groups, there was a reduction in pain scores over time. For the Co/Ac group, there was a significant reduction in the scores 12, 24, 48, and 72 hours after treatment (P<0.05). In the Tr/Ac group, the scores significantly decreased over time from time point 6 h (P<0.05). Comparing the pain at each time point, the groups were not significantly different (P>0.05), i.e., both treatments were effective in controlling pain caused by APA; however, the combination of Tr/Ac caused more adverse reactions as two patients had to stop using the medication.This study suggests that, considering both analgesic efficacy and safety, the combination of codeine and acetaminophen is more effective to control moderate to severe pain from acute periradicular abscesses. Clinical signs include swelling, edema and it is generally associated with debilitating pain,,In the treatment of APA, besides the local clinical approach, which relies on surgical access and/or root canal debridement and provide pus drainage, a systemic medication oncoming that involves the use of analgesics and antibiotics is also considered. Antibiotics can be prescribed as a complementary measure especially for abscesses associated with systemic involvement, including fever, malaise and lymphadenopathy; disseminating infections resulting in cellulitis, progressive diffuse swelling, and/or trismus; and abscesses in medically compromised patients at increased risk of a secondary infection following bacteremiaCodeine/acetaminophen is the most frequently used drug combination due to its efficacy and safety for the management of moderate-to-severe acute painThis study was approved by the Ethics Committee of the Federal University of Rio Grande do Sul (12671913.1.0000.5347).This double-blind, codeine/acetaminophen-controlled parallel design clinical trial was conducted following the Consolidated Standards of Reporting Trials (CONSORT) 2010 guideline. The sample consisted of APA patients who sought emergency care at the dental school of the Federal University of Rio Grande do Sul. Diagnosis was established based on clinical and radiographic findings. Classic symptoms of APA were obtained after subjective expressions reported by the patient.per group in order to observe a significant difference among groups.Sample size was calculated based on the outcome of Mehrvarzfar, et al.Patients eligible for inclusion in the experiment included 18+ years-old adults diagnosed with APA and reporting spontaneous pain greater than 40 mm as measured in the 0-100 mm Visual Analogue Scale (VAS) (moderate to severe pain)All endodontic procedures, performed by the same investigator (M.F.S.) were standardized. Anesthesia was induced with 2% lidocaine with epinephrine 1:100,000. Pulpal chamber was accessed under rubber dam isolation. Next, septic-toxic contents were neutralized with K files #08,10 or 15  and 2.5% sodium hypochlorite (NaOCl) . Then, the coronal portions of the canals were enlarged with a LA Axxess drill  and the work length was electronically determined by the apex locator Apex DSP . The apical part of each root canal was prepared to a size 25 K-file using a crown down technique. The canals were profusely rinsed with 5 mL of 2.5% NaOCl and dried with paper points. A sterilized cotton pellet was placed in the access cavity and subsequently restored with the glass ionomer cement Vitro Fil . Finally, the occlusion was checked.After the first appointment, the patient signed a consent form outlining the procedure and its possible risks. Subsequently, patients were allocated to one of the following groups: Co/Ac, which received one fixed-dose oral tablet containing codeine/acetaminophen (30 mg/500 mg) every 4 hours for 3 days, or Tr/Ac, which received one fixed-dose oral tablet containing tramadol/acetaminophen (37.5 mg/325 mg) every 4 hours for 3 days. Instructions on how to perform the pain recordings using the VAS were given to each patient. An assistant accompanied the patients while the first dose of medication was taken.The patients received a pain diary, containing the VAS, and a sealed package with the other doses of medication. If patients experienced pain that was not controlled by the tested medications, they were instructed to take additional medication  using under an on-demand scheme.Four days after the first visit, the patient returned the pain diary. To indirectly check adherence to the treatment plan, patients were also asked to return the medication package. Numerical values obtained at each time point  for each patient were recorded.In cases that drainage was not possible or in the presence of systemic symptoms , 21 amoxicillin capsules (500 mg) were prescribed and given orally every 8 hours for 7 days.The random allocation sequence was performed using random table numbers generated at randomizer. org. A pharmacist encapsulated the drugs in identical capsules, and packaged in white bottles numbered 1 to 26. Information on drug administration was described on the label. An assistant who was blinded to the aim and the protocol of the study generated the numbers using a spreadsheet program (Microsoft Excel).The primary outcome was the pain scores. They were obtained using VAS before and after the first appointment. Secondary outcomes included frequency of additional medication use and adverse reactions reported by patients. All information was registered in the pain diary by the patient.The Number Needed to Harm (NNH), i.e., the number of patients receiving Tr/Ac treatment to cause one additional patient to be harmed, compared with patients who received Co/Ac treatment was also calculated.The analyses were performed on an intention-to-treat basis. All statistical analyses were performed using SPSS v.18.0 .th and 75th percentiles.Descriptive statistics were performed, with presentation of data as absolute and relative frequencies, median and 25Student's t-test for independent samples was used to determine differences between the mean ages for each group. The Chi-square test was used to verify differences between the groups regarding gender, tooth type, antibiotic use and frequency of adverse reactions. Mann-Whitney U test was used to identify the difference between the mean initial pain scores between groups.The two groups were compared considering a score-based evaluation in the same time interval using the Mann-Whitney U procedure. Friedman test was used to compare the results over time within the same group, followed by the multiple comparison test of Friedman when needed. Differences were considered significant at P=0.05From April 2013 to December 2014, 27 patients were evaluated as potential study participants. Twenty-six patients met the inclusion criteria and agreed to participate in the clinical trial. Out of these 26 patients, three from the Co/Ac group and one from the Tr/Ac group did not return the pain diary and were excluded from the study. Two patients from the Tr/Ac group showed worsening clinical status, sought care elsewhere and also did not return the pain diary. Two patients from the Tr/Ac group dropped out of treatment due to the occurrence of adverse reactions that impaired their daily activities and were excluded from analysis of pain scores, but not from analysis of adverse effects . The numth and 75th percentile pain scores at each time point are shown in In both groups, pain scores decreased over time. in the Co/Ac group, pain reduction was significant at 12, 24, 48 and 72 hours compared to baseline (P<0.05). The scores at 48 and 72 hours were also lower than the 6 hours scores (P<0.05). In the Tr/Ac group, pain scores decreased in all experimental time points compared to baseline (P<0.05). The median, 25Forty percent of patients in each group used the additional drug, a number that is not different between the groups (P≈0.999). An average of 1.5 and 1.6 additional tablets per patient was used in the Co/Ac and Tr/Ac groups, respectively.There was no difference between the groups regarding the frequency of adverse reactions (P≈0.999). Eight patients (80%) from each group experienced at least one adverse reaction, including dizziness, drowsiness, nausea, headache, vomiting and others . The NNH,,,The combined use of analgesics is indicated to control pain of moderate to severe intensityThe maximum daily dosage of paracetamol is 4 grams, bearing in mind that, after the administration of 1 g, the analgesic effect wears off within an average of 6 hours. This dosage must not be exceeded, even if it becomes necessary to reduce the interval between two doses to 4 hoursIn a meta-analysis that used third molar extraction as a pain model,In the present study, no difference between the analgesic combinations with respect to pain relief was observed over 72 hours (P>0.05). Both Co/Ac and Tr/Ac treatments were able to decrease the pain scores over time. Therefore, the hypothesis set was partially accepted. In a study by Smith, et al.The frequency of additional drug use was also not a discriminating factor among groups. In both groups, four patients (40%) took additional acetaminophen. Endodontic literature lacks information about the use of additional drugs in controlling pain of endodontic origin. Some studies in other fields have measured the use of additional drugs as a way to evaluate analgesic efficacy. Da Costa-Araujo, et al.In this study, both groups presented similar frequency of adverse reactions, which is in line with the findings of Smith, et al.Opioid analgesics are useful agents for treating pain of various etiologies, however, adverse effects are potential limitations to their use. In a systematic review, Moore, et al.,,,,Most clinical trials have assessed the management of endodontic pain using a single oral dose schemeDuring the phase of abscess development, the pus is aiming to reach the exterior through the bone or periodontal tissue, which explains the pain reported by the patient. Prostration and pain lead the patient to the clinic, however, this situation does not happen and then this clinical condition remains for several days regardless the use of analgesics and antibioticsP>0.05).It is also important to emphasize that the analysis was performed on an intention-to-treat basis, as referred in the methodology. Our aim was to provide external validity to the study, since in clinical practice analgesics are prescribed to patients developing abscess that use antibiotics or not. Nevertheless, frequency of antibiotics use comparison was performed in both groups, since this could cause confusion when analyzing the analgesic response . In homoTherefore, the identification of a systemic therapy that presents an overall analgesic effectiveness as measured by its analgesic efficiency and safety is an important clinical subject to improve treatment quality of acute endodonticallyabscessed patients.The present randomized clinical trial indicated that Tr/Ac and Co/Ac treatment presented similar analgesic efficacy when used to control pain caused by APA However, Tr/Ac has a worse safety profile than Co/ Ac, resulting in a greater frequency of abandoning treatment due to ineffectiveness or intolerance to adverse effects.


This report documents six-month results of the first 50 patients treated in a prospective, multi-center study of a minimally invasive (MI) sacroiliac (SI) joint fusion system.This cohort includes 50 patients who had MI SI joint fusion surgery and completed 6 month follow-up. Average age at baseline was 61.5, 58% were female, and SI joint-related pain duration was ≥2yrs in 54.0% of patients. Visual Analog Scale (VAS) SI joint pain, Oswestry Disability Index (ODI), quality of life and opioid use were assessed preoperatively and at 6 months.At 6 months, mean VAS pain demonstrated a significant reduction from 76.2 at baseline to 35.1 , with 72% of patients attaining the minimal clinically important difference . Mean ODI improved from 55.5 to 35.3 at 6 months (p < 0.001), with 56% of patients achieving the MCID (≥15 point improvement). Prior to surgery 33/50 (66%) of patients were taking opioids, but by 6 months the number of patients taking opioids had decreased by 55% to 15/50 (30%). Few procedural complications were reported. Two procedure-related events required hospitalization: a revision procedure (2%) for nerve impingement and one case of ongoing low back pain.Analysis of patients treated with MI SI joint fusion using the SImmetry System demonstrated that the procedure can be performed safely and results in significant improvements in pain, disability, and opioid use at 6 months. Longer term follow-up in this study will determine whether these improvements are durable, as well as the associated radiographic fusion rates. With An MI SI joint fusion system incorporating decortication, bone grafting and fixation with threaded implants has demonstrated encouraging results in smaller case series , 6. This22.1This is a report of the first 50 patients participating in a prospective, multicenter evaluation of the SImmetry Sacroiliac Joint Fusion System  in the EVoluSIon study (EVSI). EVSI is to be conducted at up to 40 centers in the United States, enrolling up to 250 patients, and is registered on clinicaltrials.gov as NCT02074761. The protocol was approved by each participating center’s institutional review board and written informed consent was obtained from all patients prior to enrollment. Patients were screened from each investigator’s population of patients indicated for minimally invasive SI joint fusion. The key inclusion criteria for participation were 18 years of age or greater; at least six months of non-operative management of SI joint pain; three positive provocative tests  ; Visual Baseline data collection included medical history, prior treatments and surgeries, provocative maneuvers to confirm the diagnosis of SI joint dysfunction, diagnostic SI joint injections and pain medication usage. Eligible patients were asked to complete a questionnaire which included self-evaluation of various elements: 1) SI joint pain as measured by a VAS from 0 to 100, where 0 represented no pain and 100 represented the worst possible pain; 2) disability due to low back pain as measured by the validated ODI survey; and 3) quality of life through the EQ-5D and SF-36 questionnaires. The patient questionnaires and pain medication usage were collected pre-operatively and at specified time points of 6 weeks, 3 months, 6 months, and will be continued through 12 months, and 24 months postoperatively. Patient questionnaires were self-reported and completed by each patient prior to meeting with the investigator to limit bias. All patient qualification and endpoint data were monitored and source verified for accuracy in reporting and compliance. Data were collected and reported via electronic database .Fusion will be evaluated through collection of thin-slice computed tomography (CT) images at 12 months. Fusion assessments for the primary endpoint will be analyzed and reported after at least 50 patients have completed the 12 month visit.2.2The surgical procedure included MI SI joint fusion using the SImmetry System in accordance with approved labeling. The implant system includes a 12.5 mm diameter cannulated implant placed through the location of decortication and an 8.5 mm diameter anti-rotational implant for mechanical stability. Both are threaded implants made of titanium with a surface roughness designed for osseointegration.1): minimally invasive lateral access; joint preparation via decortication; bone graft placement; and implant delivery. The joint preparation occurs through use of a proprietary decorticator to remove cartilage and prepare up to 50% of the SI joint surface as an active bleeding fusion bed for bone graft material. Bone graft  is then packed into the decorticated area, before the cannulated implant is placed across the area of decortication. A secondary anti-rotational implant is then placed.The procedure has been described elsewhere -12. Brie2.3The primary objectives of the broader trial, of which these patients represent an initial series, are to evaluate SI joint pain relief and radiographic evidence of fusion after implantation with the SImmetry System. Ultimately two primary endpoints will be studied which include: 1) A decrease in SI joint pain from baseline to 6 month follow-up as evaluated by use of a patient-reported 100mm VAS; and 2) Radiographic evidence of SI joint fusion at 12 and 24 months post-surgery. Fusion is defined as presence of a continuous segment of solid bridging bone that extends from the sacrum to the ilium. Predefined statistical analyses described in the protocol include the primary endpoint analysis of VAS SI joint pain scores beginning with the 6-month follow-up visit. Pain relief post-implantation was evaluated at each follow-up interval with descriptive statistical analyses . Interim analyses to monitor the progress of the trial are predefined at intervals of every 50 enrolled patients at 6 months, 12 months and 24 months.VAS pain and ODI reductions were also defined in terms of minimal clinically important difference (MCID) of 20 points on the VAS scale and 15 points on the ODI scale. Multiple secondary analyses were predefined in the protocol, including assessment of ODI, EQ-5D, SF-36, procedure data, employment status, safety, and comparison of baseline and procedural data to outcomes of pain reduction and fusion. Statistical analyses to assess improvements following treatment using the pre-operative and follow-up VAS, ODI, and quality of life measures for each patient over time, using linear repeated measures models fit via maximum likelihood and a compound symmetric covariance structure, with results presented by visit and for the overall follow-up period. 95% confidence intervals on the mean changes from the pre-operative result in ODI and VAS scores were computed. Procedural data were summarized with descriptive statistics and 95% confidence intervals. Subgroup analyses for the primary endpoints were planned to determine if baseline or procedural characteristics differentiate subjects in terms of outcomes. Logistic and linear regression models were used for these analyses for the endpoints as appropriate.While 12 month follow-up results were not available at this interim analysis, the statistical analysis plan required that rates for fusion be reported as percentages of implanted subjects who show evidence of radiographic fusion at the 12 and 24 month follow-up visits.33.1The analysis cohort presented here includes the first 50 patients enrolled who had MI SI joint fusion surgery and completed a 6 month follow-up visit. This was accomplished by enrolling patients at 13 institutions. The average age at baseline was 61.5 years, the majority were female (58.0%), and SI joint-related pain duration was at least two years in 54.0% of patients. Half of the patients never used tobacco and only four patients (8.0%) were currently using cigarettes at the time of enrollment. The vast majority of patients were not working pre-surgery (82%) and many had a prior lumbar surgery (54%).1.The mean SI joint VAS pain was 76.2±11.3  and the ODI was 55.5 ±14.4 . Sixty-six percent (66%) of patients were taking opioids prior to surgery. Baseline characteristics are further summarized in Table 3.22.Fifty (50) patients underwent planned SI joint fusion surgery with the SImmetry System per the manufacturer’s instructions for use. All but one procedure (49) were unilateral; the other procedure (1) was bilateral. The average procedure time was 57 minutes (range 25 to 92 minutes) and estimated blood loss averaged 69cc. The hospital stay duration was a mean of one day with 96.0% of patients discharged within less than 2 days of the procedure. Procedural data are summarized in Table 3.3i.e., a reduction of at least 20 out of 100 points) was 72% (N=36). For patients achieving the MCID, their average reduction in pain during the same time frame was 74%.At the 6 month follow-up visit, mean VAS SI joint pain had decreased more than 41 points, from 76.2 at baseline to 35.1. This represented a statistically significant (p < 0.0001) reduction in pain of 54%. The proportion of patients attaining the MCID , demonstrating a statistically significant and clinically meaningful improvement in disability related to SI joint pain. The MCID of a decrease of 15 points was achieved by 56% (N=28) of patients. Covariate analysis of VAS and ODI outcomes with baseline and procedural characteristics did not demonstrate any statistically significant findings during this analysis.In addition to improvements in pain and disability, a significant decline in opioid use was reported. Prior to minimally invasive surgery 33/50 (66%) of patients were taking opioids, but by 6 months post-surgery the number of patients taking opioids had decreased to 15/50 . Additional evaluation of patients reporting a MCID in pain showed only 19% (7/36) of these patients continuing to use opioids 6 months postoperatively. A decrease in non-opioid pain medications was reported as well. At baseline 70.0% of patients were taking NSAIDs, 46.0% were taking other analgesics, and 22.0% were taking steroids. The percentage of patients taking NSAIDS, analgesics and steroids at the 6 month follow-up decreased to 20.4%, 22.5% and 2.0%, respectively.Quality of life assessments were collected during follow-up visits using both the EQ-5D and SF-36 questionnaires. The mean EQ-5D time trade-off index was 0.51 at baseline and increased to 0.69 (p<0.0001) 6 months post-surgery, a statistically significant change. In the same assessment, the global health thermometer rating was 56.1 at baseline compared to 68.2 (p<0.0001) 6 months post-surgery.The SF-36 includes both physical and mental components of a norm-based quality of life questionnaire. The mean physical component was 30.84 at baseline and increased to 36.41 (SD 10.52) at the 6 month time point (p=0.0001). Meanwhile the mental component changed from a mean baseline score of 42.21 to 48.50 (SD 11.34) at 6 months (p=0.0016). Both represent statistically significant improvements in this cohort.3.4Few complications related to the procedure or implanted devices were reported. Serious adverse events, including events resulting in hospitalization, were reported for two patients. One patient had radiculopathy post-surgery and nerve impingement was suggested by CT as the implanted device extended into the S1 canal. This event led to a revision procedure in which the implant was replaced with a shorter length device. Radiculopathy symptoms resolved immediately after the revision procedure. The second serious event was an ongoing case of low back pain resulting in inpatient hospitalization to manage pain.Investigators reported eight other surgical related events, but none were deemed serious in nature, nor required intervention. There was one revision (2%) in 50 patients through the 6 month visit as noted above.4>20 points) within the first 6 months post-surgery. Improvement in pain reduction was echoed in the results for disability where a statistically significant and clinically substantial improvement was reported by patients. Residual pain may be due to multifactorial degenerative lumbosacral pathology, neuroplastic effects or other inorganic causes, however was characteristic of this patient population [Early results from this prospective, multicenter trial demonstrated that MI SI joint fusion surgery with decortication, bone grafting and fixation with threaded implants resulted in an average pain reduction of 54%, and that 72% of patients had a MCID . The study population only differed in the baseline lower limits for VAS and ODI, such that SIFI enrolled patients with a minimum VAS of 50 and ODI of 30, while the current study enrolled only those with a minimum VAS of 60 and ODI of 40. Both studies are single arm, prospective, multi-center trials with a primary objective of pain reduction at 6 months, with similar data collection and follow-up intervals. The current EVSI trial has an additional primary endpoint of fusion which will be radiographically assessed by an independent core laboratory at 12 and conditionally 24 months if fusion is not yet demonstrated at 12 months. The products used in each trial have a similar indication and both implore a minimally invasive technique, which allow for a device-to-device comparison of the trial results.SImmetry is one of numerous products cleared by the Food and Drug Administration for minimally invasive implantation in patients with SI joint dysfunction. These devices are neither experimental nor investigational. While clinical trial data are not required, only a few of the 20+ implantable devices indicated for SI joint fixation have published clinical data available for comparison with the current trial. The most relevant information is from a two-year published trial with triangular titanium implants, called SIFI , 15. SIFEVSI and SIFI had similar patient populations with the primary differences being average age , gender , baseline opioid use , and sample size . Baseline VAS  and ODI  were very similar despite the differences in age, gender, opioid use and inclusion criteria. Revisions occurred in 2.0% of patients in EVSI through 6 months and 4.7% of patients in SIFI through two years. In comparing 6 month outcomes of these two trials, both achieved a statistically significant reduction in average pain compared to pre-surgery , and a reduction in disability . Both trials showed a reduction in opioid use through 6 months as well, although the EVSI cohort had a much greater reduction  , 15.The similarity in results of the EVSI and SIFI studies demonstrate that fixation of the SI joint results in pain relief, regardless of the type of implant used. It is notable that fusion rates with MI SI joint fusion systems are not well reported in the literature , in contPrevious prospective studies have demonstrated the importance of fixation of the SI joint in reducing pain and improving disability status. Comparatively, reduction in VAS pain 6 months after MI SI joint surgery has been reported as 63% and 50% with patient sample sizes of 101 and 18, respectively , 14. TheThe greatest limitations with this trial are the sample size and limited follow-up. The current data represent the first interim analysis of what will be the largest cohort of patients prospectively enrolled in a trial to evaluate both fusion and pain following MI SI joint fusion surgery. An additional 200 patients are planned to be enrolled to provide enough statistical power to determine contributing factors to fusion and pain relief. At present, this interim analysis of 50 patients provides sufficient positive outcome data to validate continuing with the trial protocol through two years of follow-up.et al. [Another limitation of this trial is a lack of a control group. The comparison of minimally invasive SI joint fixation to non-surgical therapy was previously established in a randomized trial reported by Polly, et al.  Results et al. . InsteadThis trial evaluated a 6 month endpoint for pain reduction, but clinically the ultimate goal is long-term pain relief. While implantation of SI joint devices aims to stabilize the joint, the ultimate goal is fusion of the joint to achieve long-term relief. Fusion of the SI joint has been understudied and reports of SI joint fusion range from 6 months to five years , 19-21. Minimally invasive SI joint fusion surgery with decortication, bone graft and threaded implant fixation results in pain and disability improvement through 6 months with few complications. This interim analysis demonstrates that the procedure can be performed safely, resulting in an average reduction in pain of 54%, significantly improved disability, and a substantial reduction in the use of opioids of which current use is considered a national crisis. While pain and disability improvement is comparable to similar studies, the reduction in opioid use (55%) was much greater than previously reported in other studies. Additional pain and fusion data from more patients and longer follow-up will continue to further delineate clinical and radiographic outcomes.


Mean pain level after 12 weeks of treatment was 0.20 ± 0.41. When examined according to high and low sensitivity to neurotoxic agent patients with low sensitivity had higher pain reduction, especially after 8 days after introducing treatment  and after 12 weeks . High-dose capsaicin patch is an effective treatment for pain associated with chemotherapy-induced neuropathy in patients treated with oxaliplatin. Patients with lower sensitivity to neurotoxic agents have better response to treatment and pain reduction.High-dose capsaicin patch is effective in treatment of neuropathic pain in HIV-associated neuropathy and diabetic neuropathy. There are no studies assessing effectiveness of high-dose capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy. We sought to determine the effectiveness of treatment of pain associated with chemotherapy-induced peripheral neuropathy with high-dose capsaicin patch. Our study group consisted of 18 patients with clinically confirmed oxaliplatin-induced neuropathy. Baseline characteristic including underling disease, received cumulative dose of neurotoxic agent, neuropathic symptoms, prior treatment and initial pain level were recorded. Pain was evaluated with Numeric Rating Scale prior to treatment with high-dose capsaicin and after 1.8 day and after 8 and 12 weeks after introducing treatment. Patients were divided into two groups accordingly to the amount of neurotoxic agent that caused neuropathy (high sensitivity and low sensitivity group). Most frequent symptoms of chemotherapy-induced neuropathy were: pain (88.89%), paresthesis (100%), sock and gloves sensation (100%) and hypoesthesis (100%). Initial pain level was 7.45 ± 1.14. Mean cumulative dose of oxaliplatin after which patients developed symptoms was 648.07 mg/m Chemotherapy-induced peripheral neuropathy (CIPN) is frequent complication of anti-neoplastic treatment with established frequency of 30–40% of patients undergoing chemotherapy . It signCurrently, high-dose topical capsaicin patch receives extensive attention. Capsaicin is an agonist of the transient receptor potential vanilloid receptor (TRPV1). It inhibits neural transmission in sensatory axons. Topical capsaicin patch has been proven effective for post-herpetic neuralgia , 13 and The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals of Human Use (ICH) Good Clinical Practice, current US FDA guidelines, and local ethical and legal requirements. The study was approved by the Institutional Review Boards of all participating institutions. We received permission to conduct this study from the Jagiellonian University Bioethics Committee (KBET/235/B/2014). All patients provided written informed consent.For the study, we qualified patients in stable state undergoing oxaliplatin-based chemotherapy for colon cancer who developed painful peripheral polyneuropathy, based on clinical history and neurological examination. The patients were asked to give their written consent before application of high-dose 8% capsaicin patch.Between January 2013 and February 2014, twenty-one patients with chronic pain resulting from CIPN were referred by medical oncologists to application of a high-dose 8% capsaicin patch. All the patients were assessed and qualified by a specialist in neurology and palliative medicine. A questionnaire of neuropathic symptoms was used and included questions about the presence of numbness, tingling, pain or impaired sensory function in hands and/or feet, clumsiness in fingers, peripheral muscular weakness or difficulties in walking, and the patients replied with Yes or No answers. Symptoms and signs of neuropathic pain were evaluated including a history of sensory sensations such as tingling, numbness, sharp, burning, shooting, or electric-like pain, paresthesia, allodynia, hyperalgesia and hyperpathia and motor dysfunction , myalgias or muscle cramps. Neurological examination was performed by a neurologist. The neurological examination included motor assessment (muscle strength in the limbs), sensory testing , testing of balance, coordination, and deep tendon reflexes. All patients met the inclusion criteria: age 18–72 years, diagnosed chemotherapy-induced peripheral sensory neuropathy, average pain intensity equal to or higher than 4 at screening for at least four consecutive days according to NRS, undamaged and non-irritated, dry skin at the sites of pain location, informed, written consent to participate in a clinical study. Patients were excluded when one or more of the following criteria were met: hypersensitivity to capsaicin, pregnancy, diabetes mellitus, patients with unstable or poorly controlled hypertension or a history of recent cardiovascular events (6 months) before starting treatment, patients using high doses of opioids in the treatment, patients in whom a high degree of opioid tolerance is suspected, patients in whom we observe lack of response to opioid analgesics administered orally in acute pain during the treatment procedure.The patch application process took place in a dedicated minor operation theater. The patients selected for the treatment had their dynamic pain score recorded prior to application.The patients were given a patient information leaflet prior to admission, and the procedure was explained and any concerns or questions answered. Capsaicin 8% patch was applied by a nurse and closely supervised by a physician. Skin on the application site could not be irritated, dry or intact, a topical anesthetic cream (EMLA) was applied 1 h before Qutenza patch application. The patch, which may be cut to shape, was used within 2 h of opening the foil pouch. Patients may require systemic analgesic medication or topical cooling at the site during and after treatment. They were encouraged to wear it for as long as possible, but it could be removed if the pain became intolerable. None of the adverse events occurred.Efficacy was measured using an 11-point Numerical Rating Scale (NRS) with 10 representing the worst pain imaginable and 0 representing no pain. Initial pain level was taken before administrating capsaicin patch and after 1 and 8 days after administration and after 8 and 12 weeks after administration of the patch.2 Pearson’s test to compare proportions. T test and Mann–Whitney U test were used as appropriate to compare continuous variables. All statistical calculations were preformed using STATISTICA 10.0 v.  software for Microsoft Windows.Elements of descriptive statistics were used . We used χAverage pain score was 4 or above during the screening period, over a minimum of at least four consecutive days .2; however, the beginning dose after which the symptoms of polyneuropathy appeared was 648.07 mg/m2. Average initial pain intensity was assessed at 7.67 ± 0.51 points in the group.Eighteen patients were included into the study. All the patients received treatment according to the scheme and were involved in the evaluation of efficacy and safety. Among patients enrolled in the study, there were 12 women and 6 men, with a mean age of 62 years. Mean cumulative neurotoxic dose was 832.9 mg/mBecause of the symptoms of chemotherapy-induced neuropathy in the period preceding the application of the patch 9 people did not receive any treatment for neuropathic pain. The treatment received by others is presented in Table 2 of oxaliplatin was, respectively, 28% after the first day and 84% at 12 weeks after application of the patch. In the second group of patients in whom the symptoms appeared after the treatment with higher cumulative doses of oxaliplatin, reduction of pain was, respectively, 33% after the first day and 97% after 12 weeks. Statistical analysis of the results of the research shows a statistical significance between the treated groups of patients, which show as considerably higher levels of pain reduction after 8 days and 12 weeks for patients with the used cumulative doses (average of 20% after 8 days and about 14% after 12 weeks). The main measure of effectiveness was reduction of pain as measured by 24-h NRS pain assessment scale for up to 12 weeks after application of the patch. After the application of the patch, statistically significant reduction of pain in NRS scale was obtained, respectively, after 8 days in the first group with symptoms occurring <648.07 mg/m2 of oxaliplatin 3.83 and 2.25 in the second group (p = 0.02). After 12 weeks following the application of Qutenza patch, patients achieved a reduction of at least 1.16 in NRS score in the first group compared with 0.25 of the second group (p = 0.04). All the results are presented in Table In the 12-week study, pain reduction in patients whose initial symptoms occurred after the administration of 648.07 mg/mIn our study, we described efficacy and safety of high-dose 8% capsaicin patch in treatment of patients with chemotherapy-induced peripheral neuropathy in patients treated with oxaliplatin-based chemotherapy for colon cancer. Total reduction of pain ranged between 84 and 97% assessed at 12 weeks. Furthermore, we observed no adverse events showing that high-dose capsaicin is safe and effective way to treat CIPN.Effectiveness of high-dose 8% capsaicin is well established in treatment of HIV-associated neuropathy and post-herpetic neuralgia . ResultsCertain authors attempted to determine possible predictors of treatment response to treatment with high-dose 8% capsaicin. Katz et al.  found thOur study has certain limitations. Firstly, our study population was only 18 patients and was limited by the amount of founding for off-label use of patches that we were able to provide. Second limitation that our study group was not examined by standardized questionnaires such as Brief Pain Inventory or McGill Pain inventory. On the other hand, all of patients were examined by a board-certified neurologist. This raw data show much more detailed signs and symptoms specific to neuropathic patients. Most of the standardized questionnaires do not include such specific symptoms. We are confident that in term of presenting neuropathic patients symptoms detailed neurological examinations have deeper significance. Thirdly, we were able to present only observation period of 12 weeks, not being able to determine the total length of effect of the treatment. We are planning to do so in further studies.To the best of our knowledge this is the first study attempting to determine the use of high-dose 8% capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy.