Purpose. To analyze leg pain severity data from a randomized controlled trial (RCT) of lumbar disc surgery using integrated approaches that adjust pain scores collected at scheduled follow-up visits for confounding clinical events occurring between visits. Methods. Data were derived from an RCT of a bone-anchored annular closure device (ACD) following lumbar discectomy versus lumbar discectomy alone (Control) in patients with large postsurgical annular defects. Leg pain was recorded on a 0 to 100 scale at 6 weeks, 3 months, 6 months, 1 year, and 2 years of follow-up. Patients with pain reduction ≥20 points relative to baseline were considered responders. Unadjusted analyses utilized pain scores reported at follow-up visits. Since symptomatic reherniation signifies clinical failure of lumbar discectomy, integrated analyses adjusted pain scores following a symptomatic reherniation by baseline observation carried forward for continuous data or classification as nonresponders for categorical data. Results. Among 550 patients , symptomatic reherniation occurred in 10.3% of ACD patients and in 21.9% of controls (p < 0.001) through 2 years. There was no difference in leg pain scores at the 2-year visit between ACD and controls  in unadjusted analyses, but statistically significant differences favoring ACD  in integrated analyses. Unadjusted nonresponder rates were 6.0% with ACD and 6.7% with controls (p = 0.89), but 15.7% and 27.8% (p = 0.001) in integrated analyses. The probability of nonresponse was 16.4% with ACD and 18.3% with controls (p = 0.51) in unadjusted analysis, and 23.7% and 31.2% (p = 0.04) in integrated analyses. Conclusion. In an RCT of lumbar disc surgery, an integrated analysis of pain severity that adjusted for the confounding effects of clinical failures occurring between follow-up visits resulted in different conclusions compared to an unadjusted analysis of pain scores reported at follow-up visits only. Long-term follow-up in clinical trials is mandatory for monitoring the safety and efficacy of chronic pain treatments. However, longer follow-up periods also increase the likelihood for missing data, patient withdrawal, and clinical events that may confound data interpretation. Numerous analytic approaches are available to deal with missing data  and their comparative performance and recommendations for use are well-documented –3. HowevTake, for example, a clinical trial of lumbar disc surgery with annual follow-up visits for 5 years. A patient reports pain severity of 20 on a 100 mm visual analogue scale (VAS) at 1-year follow-up, undergoes repeat discectomy at 1.5 years due to increasing pain and disability from reherniation, and reports back pain severity of 20 at the scheduled 2-year follow-up visit (6 months after reoperation). In this instance, how should pain scores be treated in the analysis? Excluding data from patients who undergo reoperation is an inherently biased method of analysis. Analysis of pain scores reported only at the annual follow-up intervals fails to account for the implicit episode of increased pain and eventual clinical failure  occurring during the interim period. Further, the 2-year pain scores reported in this example are mainly attributable to the reoperation, not to the index surgery. Thus, in clinical trials of pain treatments with planned long-term follow-up, confounding clinical events occurring during the interval between scheduled visits should be taken into account in data analysis. The purpose of this study was to analyze leg pain severity data from a clinical trial of lumbar disc surgery using integrated approaches that adjusted pain scores collected at scheduled follow-up visits for confounding clinical events that occurred between visits.NCT01283438). The study design [Data were derived from a multicenter randomized controlled trial intended to determine whether implantation of a bone-anchored annular closure device (ACD) in patients with a large annular defect following lumbar discectomy reduced the risk of recurrent herniation compared to lumbar discectomy alone (controls). The clinical trial was approved by the local ethics review boards, and all participants provided written informed consent. This study was prospectively registered at ClinicalTrials.gov NCT0128338. The sy design  of this y design .Leg pain severity in postsurgical follow-up was recorded on a 100 mm VAS scale at scheduled visits  using a 1-week recall period. Importantly, pain experienced by patients in the period between follow-up visits was not quantitatively recorded. Patients reporting pain reduction of at least 20 points relative to baseline were considered responders. Symptomatic reherniation was defined as a recurrent herniation that was surgically verified during reoperation, reported as an adverse event, or identified by the imaging core laboratory in conjunction with the patient reporting moderate disability (ODI ≥ 40), radicular symptoms, or neurologic deterioration.A modified intent-to-treat population was analyzed that included all randomized patients in whom the intended procedure was attempted. We analyzed leg pain data in four different ways, with two methods utilizing continuous data (leg pain VAS) and two methods utilizing categorical data (responder versus nonresponder). For each method, we drew comparisons between unadjusted and integrated results. Unadjusted analyses of group means and nonresponse rates utilized pain scores reported at scheduled follow-up visits. Integrated analyses considered patients with symptomatic reherniation as clinical failures. For integrated analyses of continuous data, we used a BOCF approach where the baseline observation was carried forward to adjust pain scores at all subsequent follow-up visits. This method was selected since symptomatic reherniation signifies clinical failure of lumbar discectomy and because VAS pain scores at the time of reherniation are comparable to the baseline VAS scores attributable to primary herniation in the current study . For int p < 0.05 and hypothesis testing was two-sided. Statistical analyses were performed using SAS v9.4 (SAS Institute).Group comparisons of mean leg pain scores at 2 years were performed using an independent-samples t-test. We additionally performed a repeated-measures linear mixed model, which is more robust since it considers all available leg pain scores that were reported after randomization and can flexibly include patients with missing data. The proportion of nonresponders in each group at 2 years was analyzed using Fisher's exact test. Time to first nonresponse was reported as a cumulative probability using Kaplan-Meier methods, with log-rank tests for group comparisons. In all analyses, statistical significance was set at p < 0.001) through 2 years.Between December 2010 and October 2014, 554 patients were randomly assigned to ACD (n=276) or control (n=278). The modified intention-to-treat population included 550 patients  owing to 4 patients who were randomized to ACD but in whom implantation was not attempted because of anatomical constraints. Treatment groups were well matched at baseline. The mean age of the study population was 43 years and 59% were men. Surgery was performed at L4-L5 or L5-S1 in 97% of patients. Compliance with clinical follow-up at 2 years was 91% in each group. The frequency of symptomatic reherniation was lower with ACD versus controls . However, the integrated analysis revealed statistically significant differences in 2-year pain scores favoring the ACD group  ( p = 0.06). However, the integrated analysis revealed statistically significant differences in pain score changes favoring the ACD group   between ACD and controls at the scheduled 2-year follow-up visit  . In the < 0.001) .p = 0.89). In integrated analyses, the corresponding nonresponder rates were 15.7% and 27.8%, respectively (p = 0.001) (p = 0.51) in unadjusted analysis. In integrated analysis, the corresponding cumulative nonresponse rates were 23.7% with ACD and 31.2% with controls (p = 0.04)  . The cum = 0.04) .Objective and accurate measurement of pain remains a challenge in longitudinal clinical trials. Patients with degenerative spinal conditions may experience fluctuating symptoms that may not be present at scheduled follow-up visits. In this randomized controlled trial of lumbar discectomy with or without additional ACD implant, over 90% of patients in each group reported leg pain scores indicative of clinical success at 2-year follow-up, with no differences between groups. However, simply analyzing patient-reported outcomes without consideration for confounding clinical events occurring between visits will underestimate the true rate of clinical failure. In the current study, patients with symptomatic reherniation undoubtedly experienced an episode of significant pain during follow-up that was not necessarily present on the date of the scheduled follow-up visits given the 1-week recall period of the VAS pain tool. In all integrated analyses, there was a significant reduction in leg pain with ACD versus controls. These discordant results highlight the inadequacy of relying on pain scores derived solely from fixed annual follow-up intervals for clinical decision-making since most patients that experienced symptomatic reherniation during follow-up were still considered responders in the unadjusted analyses since most underwent a reoperation that biased 2-year pain scores.An FDA recommendation for analgesic studies is development of an integrated analgesic assessment score that combines information from patient pain scores with the amount of morphine administered via patient-controlled analgesia pumps –10. OtheInterestingly, the percentage of patients who required opioid analgesia at 2-year follow-up was approximately 50% lower in the ACD group versus controls. Unfortunately, these data were not collected with sufficient detail to calculate and compare equianalgesic opioid doses between groups. Nonetheless, it appears that the analysis of patient-reported pain scores may have underestimated the utility of ACD in decreasing episodic pain due to reherniation. Even the integrated analyses that accounted for clinical failures may continue to underestimate the treatment benefit since results in the ACD group were achieved with less opioid use. Future studies should implement more detailed accounting of postoperative opioid consumption, which could be used to adjust pain scores or to define a pain nonresponder if analgesia was achieved due to chronic, high-dose opioid use.In addition to more refined analysis algorithms, more robust data collection methods could be implemented to more accurately characterize the long-term clinical course of a fluctuating condition such as sciatica. However, any initiatives to collect a greater frequency or volume of data must simultaneously avoid overburdening the patient with time-consuming questionnaires or demands for excessive on-site visits, both of which may result in the opposite of the intended effect due to patient noncompliance. Web- or phone-based questionnaires have been shown to be reliable and user-friendly and have high completion rates, which may be ideal for collecting data at more frequent intervals –14. Data post hoc in nature and should be considered exploratory. A second limitation is that imputing baseline scores at all follow-up visits following a report of symptomatic reherniation may be viewed as overly conservative. However, since all patients in this trial underwent lumbar discectomy for symptomatic lumbar disc herniation, symptomatic reherniation clearly represented failure of the primary procedure and was therefore accounted for in the analysis. The merits of this argument are obviously debatable yet seemed the most reasonable for illustrating the limitations of reporting pain scores in isolation without clinical consideration. Finally, we do not propose a single integrated analysis method for future studies, but instead present these data to highlight current limitations of pain reporting in clinical trials and to encourage additional research on this topic.A limitation of this study is that most analyses presented here areIn a randomized controlled trial of lumbar disc surgery, an integrated analysis of pain severity that adjusts for the confounding effects of clinical failures results in different conclusions compared to an unadjusted analysis of pain scores reported at routine follow-up visits. Initiatives to develop more rigorous data collection methods and to develop composite pain outcomes combining patient-reported and clinical information collected throughout the study, not just at fixed intervals, are encouraged in clinical trials of degenerative spinal conditions. Such efforts may enhance physician and patient understanding of therapeutic efficacy and avoid misleading conclusions.


Non-cardiac chest pain is common and there is no formal recommendation on what diagnostic tests to use to identify underlying diseases after an acute coronary syndrome has been ruled out.To evaluate the diagnostic tests, treatment recommendations and initiated treatments in patients presenting with non-cardiac chest pain to the emergency department (ED).Single-center, retrospective medical chart review of patients presenting to the ED. Included were all medical records of patients aged 18 years and older presenting to the ED with chest pain and a non-cardiac discharge diagnosis between January 1, 2009 and December 31, 2011. Information on the diagnosis, diagnostic tests performed, treatment initiated and recommendation for further diagnostic testing or treatment were extracted. The primary outcomes of interest were the final diagnosis, diagnostic tests, and treatment recommendations. A formal ACS rule out testing was defined as serial three troponin testing.In total, 1341 ED admissions for non-cardiac chest pain  were analyzed. Non-specific chest pain remained the discharge diagnosis in 44.7% (n = 599). Identified underlying diseases included musculoskeletal chest pain , pulmonary , GI-tract , or psychiatric diseases . In 81.4% at least one troponin test and in 89% one ECG were performed. A formal ACS rule out troponin testing was performed in 9.2% . Most frequently analgesics were prescribed (51%). A diagnostic test with proton pump inhibitor (PPI) was prescribed in 20% . At discharge, over 72 different recommendations were given, ranging from no further measures to extensive cardiac evaluation.In this retrospective study, a formal work-up to rule out ACS was found in a minority of patients presenting to the ED with chest pain of non-cardiac origin. A wide variation in diagnostic processes and treatment recommendations reflect the uncertainty of clinicians on how to approach patients after a cardiac cause was considered unlikely. Panic and anxiety disorders were rarely considered and a useful PPI treatment trial to diagnose gastroesophageal reflux disease was infrequently recommended. The top priority in patients presenting with chest pain to the emergency department (ED) is to rule out a potentially life-threatening disease such as an acute coronary syndrome (ACS), pulmonary embolism, aortic dissection, or pneumonia. After a thorough diagnostic work-up, an acute myocardial ischemia can be ruled out for 60% to 90% of patients presenting with chest pain –4. WhilePatients with NCCP can be categorized in patients with and without an identifiable underlying disease (i.e. non-specific chest pain). It has been suggested that up to 50% of the patients discharged with NCCP have an underlying gastrointestinal reflux  or a psyTherefore, the clinical challenge is to determine which diagnostic tests to apply in patients with chest pain after a cardiac disease has been ruled out in order to discriminate between patients with non-specific chest pain and other underlying diseases presenting with NCCP. For example, a high dose proton pump inhibitor (PPI) treatment trial may be useful to identify patients with underlying gastroesophageal reflux disease (GERD) and screening tools may identify patients with an underlying panic or anxiety disorder . To dateThe objective of this retrospective study was to gather knowledge about the diagnostic steps in the ED and the treatment recommendations for patients discharged from the ED with a diagnosis of NCCP. We analyzed the frequency of discharge diagnoses, the performed diagnostic tests, the initiated treatments, and the treatment recommendations. We hypothesized that the majority of patients were discharged with a musculoskeletal or non-specific disease and the diagnostic assessment focused mainly on ruling out of an ACS. Further, we hypothesized that a high-dose PPI treatment trial to identify patients with GERD related chest pain was infrequently used and psychiatric diseases rarely considered.Single-center, retrospective medical chart review of patients presenting to one of the ten largest hospitals in Switzerland, the Cantonal Hospital Winterthur, between January 1, 2009 and December 31, 2011. The study period was chosen because an outpatient clinic opened in 2012 and therefore, many patients eligible for this study were potentially treated elsewhere. The hospital is affiliated to the University of Zurich and covers the medical services for approximately 200'000 persons (15 percent of the inhabitants of the canton Zürich).Potentially eligible medical records were identified by using prespecified diagnostic German International Classification of Disease Version 10 (ICD-10-GM) codes coded by ED physicians: R06.4 (hyperventilation), R07.1 (chest pain when breathing), R07.2 , R07.3 (other chest pain), and R07.4 (chest pain not further specified).2) as well as patients with incapacitation or records of patients which opted out of releasing their records for scientific purposes.Included were all medical records of patients age 18 years and older presenting to the ED with chest pain and a non-cardiac discharge diagnosis between January 1, 2009 and December 31, 2011. Excluded were patients with chest pain of cardiovascular origin, pregnant women, trauma patients or life-threatening conditions, malignant disease, current fracture, renal replacement therapy or severe kidney failure  for inclusion or exclusion. In case of uncertainty, the records were discussed with the principal investigator (MW) and disagreement was resolved within the research group. Each patient included in the study was assigned a unique de-identified number. We defined the first presentation for chest pain to the ED as the index consultation for the first episode. During the following three months each presentation  was considered potentially related to the index consultation and was defined as a follow-up consultation. Presentations to the ED or hospitalizations after more than three months due to chest pain were defined as a new index visit of a second episode.Variables of interest were predefined and the extraction form was pilot-tested in 20 records. To ensure high quality in the data extraction, TD and SM were trained and monitored by MW and an extraction manual was used. We extracted information on general characteristics , cardiovascular risk factors, signs and symptoms at presentation, preexisting comorbidities, medications, clinical findings at presentation, blood analyses, ECG, imaging studies, coronary angiography, non-invasive testing  and other tests/investigations. Further information on discharge medications, discharge diagnosis, recommended procedures / investigations after discharge were extracted.The main study endpoints of interests were the final diagnosis, performed diagnostic tests, and treatment recommendations. The final diagnosis was based on the discharge diagnosis extracted from the discharge letters. In patients with re-visits to an outpatient clinic or the ED any additional follow-up assessment and reports were reviewed and screened for changes in the discharge diagnosis. In patients with differences between the discharge diagnosis and the diagnosis on follow-up visits, the final diagnosis was adjudicated by a research committee –blinded to the details of index visit–based on the results of the follow-up evaluation and records of re-hospitalizations. Each final diagnosis was assigned to one of the five categories: musculoskeletal chest pain, gastrointestinal chest pain, pulmonary chest pain, chest pain in psychiatric diseases, and non-specific chest pain.We defined a formal ACS rule out testing as serial troponin tests performed at presentation, a second (after 3 to 6 hours), and a third (beyond 6 hours) . AdditioThe quality of the data extraction was assessed by a researcher not involved in the extraction process (BK). In total, six predefined parameters  in 379 ED visits were reviewed. The quality of data extraction was high with an error rate of 5.4% (95% CI 4.5–6.4).We calculated median and interquartile ranges for continuous variables, numbers and percentages of total for binary or categorical variables. A chi-squared test was used for group comparisons for categorical variables and Kruskal-Wallis test was used for continuous variables between groups. Differences between the diagnostic categories were visualized using bar plots. All analyses were performed with the statistical software R .Due to the retrospective nature of the study, data extraction did not interfere or influence the treatment of patients. The study was approved by the independent Ethics Committee of the Canton Zurich, Switzerland  and complied with international standards including the declaration of Helsinki, good clinical practice, and the Swiss law for research in human subjects.Table 1) were finally analyzed. The main discharge diagnoses were musculoskeletal chest pain  and non-specific chest pain . Musculoskeletal diagnosis were mainly non-specific related to the chest wall (90%) or to the spine (3%). Specific musculoskeletal diagnosis were found in a few patients . In a small proportion of patients the diagnostic work-up resulted in a pulmonary , GI-tract , or psychiatric diseases .Out of 31,902 visits to the ED, 2,438 records with the ICD-10 codes R07.1–4 were screened and 1,341 ED admissions for non-cardiac chest pain . Cardiovascular disease was known in 34.2% , a history of peripheral arterial disease in 0.8%, stroke in 1.9%, and diabetes mellitus in 5.1%. Overall, 32% of the patients met the definition for multimorbidity (≥ two known diseases). Further details are summarized in Table 1 and The majority of patients were female (55%), married (58%), and the median age was 46 years . The diagnostic work-up with regards to vital signs was comparable in all categories: blood pressure measurements in 91.6%, oxygen saturation or the respiratory rate in 74.8%, and body temperature in 51.1%. Overall, in 89% of the patients an ECG, in 91.9% at least one blood analysis, and in 81.4% at least one troponin test was performed. Fig 1 shows the proportion of patients for each diagnostic group with initial and follow-up troponin testing. The proportion of initial troponin testing varied between 90% (non-specific chest pain 90.3% and GI-diseases 90.4%) and below 75% . A second follow-up troponin test was performed in 42.7% and a formal ACS rule out with a third troponin test in 9.2% (Table 2 and S2 Table). The formal ACS rule out testing was performed in patients with GI-tract diseases (14.3%), non-specific chest pain (14.0%), pulmonary diseases (10.0%), musculoskeletal chest pain (4.7%), and psychiatric diseases (4.0%).Diagnostic evaluation was mainly performed on an outpatient basis . Around 10% of all patients were hospitalized (0.4% in an intensive care unit). Additional evaluation using a tread mill test was performed in 2.6%, echocardiography in 4.8%, MIBI scintigraphy in 0.7%, and coronary angiography in 3.0%. Table 3 the most frequent recommendations and initiated treatments are summarized. In 17% of the patients further cardiac evaluation  was recommended followed by a GP follow-up or a GP initiated assessment/action (16.6%). In patients with non-specific chest pain cardiac evaluation and GP follow-up was most often recommended . Whereas a psychiatric evaluation was recommended in very few patients (<1%), anxiolytics or psychological treatment was most often initiated in patients with psychiatric discharge diagnosis (18.7%).Overall, 76 different recommendations at discharge were identified. In Fig 3 shows the differences in the use of medications. The highest proportion of PPI use was found in patients with GI-tract disease (71.4%) and non-specific chest pain diagnoses (25.7%). Antipsychotics were used in 15.4% of the patients with the majority in patients with psychiatric diagnoses (25.3%).Newly initiated acetylsalicylic acid (ASS) treatment was found in 3.5% and for statins in 2.3% of patients. Analgesics were used by 51% of all patients . The most frequently newly prescribed analgesic was paracetamol (30.4%), followed by NSAIDs (23.2%), and metamizole (17.2%). PPI use was found in 20.5% of patients. Recurrent visits were recorded in 13.1% mainly with emergency readmissions (8.1%) and outpatient visits (3.3%). Whereas 50% were related to the first emergency visit, 50% were due to other reasons. The highest proportion of related visits was found in patients with pulmonary chest pain (23.3%) and a GI-tract disease (20%). Technical evaluations in the outpatient setting at the same hospital were found in less than 5% of the patients.The major finding of this study is that chest pain of non-cardiac origin accounted for 4.2% of all ED visits and the diagnostic evaluation included in a minority of patients a formal cardiologic work-up with sequential cardiac troponin testing. In the majority of patients musculoskeletal chest pain or a non-specific chest pain was the discharge diagnosis and psychiatric diseases were rarely considered. Over 72 different recommendations at discharge were given, ranging from no further measures to extensive cardiac evaluation. Despite the recommendation for cardiologic follow-up evaluation in one fifth of the patients, ASS treatment was initiated in only a small proportion of those patients. The most frequently initiated treatment was analgesics where mainly paracetamol was prescribed. A diagnostic test with proton pump inhibitor was prescribed in 20% of patients without specific recommendations about the follow-up assessment.NCCP account for a relevant number of emergency department visits. The prevalence of NCCP reported in this study was comparable to a previous study where patients with NCCP accounted for 5% of all ED visits . In the Proton pump inhibitor treatment trials are highly effective to identify patients with underlying gastroesophageal reflux diseases . FurtherThis study showed that a primary focus to rule out an acute coronary syndrome (ACS) by extending ECG and cardiac troponin testing to all patients with chest pain in an ED may result in more diagnostic tests without improving the diagnostic and treatment algorithm in the majority of patients. It is important to consider that patients can have elevated troponin levels without cardiac diseases and elevated troponin test may result in more downstream testing without clinical utility . In our To the best of our knowledge, this was the first study that assessed diagnostic processes and treatment recommendations in patients with NCCP. We found a lack of clinical concepts to assess and treat patients with chest pain after an ACS has been ruled out. Other strategies shown to be effective or useful were not recommended by physicians. For example, a positive response to a high dose PPI treatment trial for one or two weeks indicates an underlying GERD whereas a negative response rules out GERD and can help primary care physicians to further evaluate their patients , 28. AccWhile this study was conducted using rigorous predefined protocols and the data extraction quality was high, there are limitations to consider.The main limitation is the retrospective nature of this study. Patients were identified by ICD-10 codes for non-specific chest pain and therefore, patients with other diseases presenting with chest pain may have been missed. However, the prevalence of patients with NCCP reported in this study was comparable to a previous study . While gThis study has several implications for future research. Future studies should assess the impact of a structured evaluation and treatment recommendation in patients with chest pain after an ACS has been ruled out. To prevent overdiagnosis and overtreatment, studies that assess the efficacy of clinical prediction rules to rule out ACS should be compared to clinical judgment by emergency department physicians. It has been shown that the clinical judgment by ED physicians was at least equally accurate to rule in or out an ACS compared to the HEART score, a prediction rule developed in ED patients with chest pain .In patients with non-cardiac chest pain, panic disorders and GERD are rarely considered in the treatment recommendations. This study underscores the need for guidance in patients with non-specific chest pain. Patients with chest pain of unknown or unspecific origin may express avoidance and anxiety symptoms . A strucIn this retrospective study a formal work-up to rule out ACS was found in a minority of patients presenting to the ED with chest pain of non-cardiac origin. A wide variation in diagnostic processes and treatment recommendations reflect the uncertainty of clinicians on how to approach patients after a cardiac cause is considered unlikely. Panic and anxiety disorders were rarely considered and a useful PPI treatment trial to diagnose gastroesophageal reflux disease was infrequently recommended.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


Interstitial Cystitis (IC) is a chronic condition diagnosed based on the presence of symptoms, such as suprapubic/ pelvic pain, pressure or discomfort in association with urgency and increased urinary frequency. Confusable diseases must be excluded. However, there is no objective test or marker to establish the presence of the disease. Diagnosis and patient management is often difficult, given the poor understanding of IC pathogenesis and its unknown etiology and genetics. As an attempt to find biomarkers related to IC, we assessed the association between 20 selected single nucleotide polymorphism (SNPs) with IC and pain severity.To assess the presence of SNPs in IC patients’ blood samples and correlate them with the disease and chronic pain condition.A case-control study was conducted. We selected 34 female patients with IC diagnosed according to NIDDK criteria and 23 patients in the control group . IC patients were allocated into two groups according to reported chronic pain severity. We selected the following SNPs for analysis: rs1800871, rs1800872, rs1800896, rs1800471, rs1800629, rs361525, rs1800497, rs6311, rs6277, rs6276, rs6313, rs2835859, rs11127292, rs2243248, rs6887695, rs3212227, rs1799971, rs12579350, rs3813034, and rs6746030. Genotyping was performed by real-time PCR (q-PCR).The polymorphic allele of SNP rs11127292 exhibited a higher frequency in subjects with IC than in controls (p:0.01). The polymorphic allele of SNP rs6311 was more frequent in patients with severe pain (p:0.03). The frequency of the wild-type allele of SNP rs1799971 was higher in patients with mild to moderate pain (p:0.04).The results indicated differences in SNP frequency among subjects, suggesting that SNPs could serve either as a marker of IC or as a marker of pain severity in IC patients. The study showed promising results regarding IC and polymorphism associations. These associations have not been previously reported. Interstitial Cystitis (IC) or Painful Bladder Syndrome (PBS) is a debilitating chronic pelvic pain condition primarily based on symptoms of bladder-related pain, urgency, frequency and nocturia. The etiology is still unknown. Any other confounding urologic disease must be excluded ,2. InitiHowever, there is no established objective marker or test to define this disorder, persisting a diagnosis of exclusion. Associations with other chronic pain conditions have been commonly described, and pain has been reported as the most debilitating symptom degrading quality of life –10.Given that many associated clinical conditions have been described regarding IC/PBS, it is reasonable to assume that there are probably many underlying common physiopathologic pathways among these diseases ,10.IC/PBS have been historically considered a heterogeneous syndrome with intricate diagnosis and a wide variety of presentations and phenotypes. Several studies have failed to identify both the etiology and disease biomarkers, in part because few genetic studies have been conducted –16.Warren et al showed a 17 times higher prevalence of IC/PBS among first-degree related adult women than in the general population. These authors have previously shown a higher prevalence of the disease among monozygotic twins. ExperimOur goal is to evaluate the genetic variations and individual phenotypic differences related to IC/PBS and its clinical severity based on pain symptoms.Understanding genetic associations and their relationship to the phenotype is essential for the comprehension of diseases and human variety. In light of new advances in genetic understanding and technology, we conducted a prospective case-control study focusing on single nucleotide polymorphisms (SNPs) and their possible association with IC/PBS diagnosis and severity based on pain symptoms. Single nucleotide polymorphisms are the most common genetic variant and, once functional, may be the underlying clinical variations. In this present study, we tried to reveal the relationship between the SNPs associated with IC/PBS and the individual differences in pain experienced among the IC/PBS subjects.The identification of SNPs associated with a disease may help to explain the disease etiology and serve as a genetic biomarker.Subjects in both groups provided written informed consent to participate the study and allowed their biological samples to be genetically analyzed. Approval for the study was given by the Institutional Board of Ethics (CAPPesq–Comissão de Ética para Análise de Projetos de Pesquisa) under the number 796/015.A case-control study was conducted. Patients with IC/PBS defined according to NIDDK  criteria  and low-To define low-comorbid disease, the following conditions were considered exclusion criteria: Fibromyalgia, Irritable Bowel Syndrome, Vulvodynia, Temporomandibular Dysfunction and Orofacial Pain, suspected endometriosis, symptoms of bladder outlet obstruction, genital prolapse and symptoms suspected to be related to pudendal nerve compression or pelvic floor musculature-related pain. American College of Rheumatology (ACR) questionnaires were used to exclude any patient not diagnosed with fibromyalgia at the time of the screening appointment.The prevalence of the selected SNPs was compared among the IC and control groups. This was the primary objective.Second, IC/PBS females were stratified into two groups according to pain severity. This secondary objective was aimed to evaluate pain severity among IC/PBS patients, irrespective of bladder lesion severity. Pain is a subjective and multifactorial symptom. Pain questionnaires were applied, in every office appointment, in order to graduate the intensity and to minimize its subjectivity. Considering its underlying genetic background and the absence of correlation of pain severity to bladder lesion findings, evaluation of polymorphisms seems to be appropriated. Bladder-related pain was observed as the most disabling symptom and was presented in every IC/PBS patient studied.High intensity pain perception was considered either a pain score of 7 or more or a McGill pain classification as exhausting, vicious, killing, wretched, blinding or unbearable. Patients were stratified based on pain severity data obtained from the worst pain experience reported during office follow-up.All enrolled females were patients referred to the Female Urologic Division of our Institution. During regular appointments, patients were screened. Following the initial appointment, the study was explained and an Informed Consent was obtained from patients interested in participating the study.All participants enrolled were submitted to a comprehensive medical evaluation. Routine blood and urine samples analysis, urinary ultrasonography and urodynamic evaluation were performed. Cultures were negative. Questionnaires were applied. Clinical and demographic data were considered regarding age, timing of symptoms onset, comorbidities, symptom severity, previous treatments and quality of life index. The Interstitial Cystitis Symptom Index and Problem Index , and TheAll IC/PBS females underwent cystoscopic evaluation, with bladder biopsy and urinary cytology performed only when individually indicated, based upon cystoscopic findings. All patients underwent bladder distention under general anesthesia.In general, the average age of IC/PBS patients was 50,5 years. All patients of the study were Brazilian and most white females. Only one patient showed Hunner’s lesion on cystoscopy, which was treated with transurethral cauterization. All other patients presented glomerulations after bladder distension.Cystoscopy and hydrodistension under anesthesia were fundamental to the completion of NIDDK criteria and to exclude confusable diseases.We selected 20 polymorphisms (SNPs), according to a PubMed database search using the terms: “single nucleotide polymorphism”, “polymorphism”, “SNP” and “pain”, “pain syndrome”, “inflammation”, “anxiety”, “depression”, “psychiatric syndrome/disease”, “fibromyalgia” “inflammatory bowel disease”, “migraine”, “headache”, “bladder”, “frequency”, “urgency”. Genomic DNA was extracted from blood samples using QIAmp DNA Blood Mini Kit (QIAGEN). The SNPs were genotyped using a TaqMan SNP Genotyping Assay Kit and an ABI 7500 fast system .SNP-specific polymerase chain reaction (ss-PCR) primers  and fluoThe target sequence was amplified in a 10 μl reaction volume that contained 5 μl of Taq-Man1 Universal PCR Master Mix, 0.25 μl of SNP Genotyping Assay (primers and probes), 1 μl of genomic DNA, and 3.75 μl of DNase-free water. The PCR cycling conditions were 2 minutes at 50°C and 10 minutes at 95°C, followed by 40 cycles of 15 seconds at 95°C and 60 seconds at 60°C. After PCR amplification, an endpoint plate reading was performed using an Applied Biosystems 7500 fast Real-Time PCR System. Sequence Detection System (SDS) software uses the fluorescence measurements made during the plate reading to plot fluorescence (Rn) values based on the signals from each well. The plotted fluorescence signals indicate which alleles are in each sample.TaqMan SNP Genotyping Assay overview, representing the two primers and the two MGB probes annealing specifically to a complementary oligonucleotide sequence presented in the polymorphism. Each probe is specific to a given SNP allele . Each probe end has an attached molecule, a fluorescent molecule (dye reporter) at one end, and a non-fluorescent molecule at the other (dye quencher). When the probe is intact, the proximity of the quencher dye to the reporter dye suppresses the reporter fluorescence. During the PCR cycles, Taq DNA polymerase exonuclease activity cleaves only the probes hybridized to the target, separating the reporter dye from the quencher dye, increasing the fluorescence of the reporter. .2) comparing the difference between the patients and controls. Statistical significance was considered at p < 0.05 .Statistical methods were performed using SPSS 19.0. Univariate analysis was done using chi-square test .PCR products from the 20 selected SNPs were detected in all DNA specimens from 34 IC/PBS patients and 23 controls. Genotypes and allele distribution were compared.The genotype results are presented in The allele distribution is presented in IC/PBS females were further allocated into two subgroups according to pain severity symptoms (McGill and VAS). Group 1 comprised 12 females with mild to moderate pain and group 2 comprised 21 IC patients with severe pain. The genotypes and allele distribution were compared and presented in Genotype distribution failed to show any significant difference between the two groups.Data considering SNP rs6311 revealed a significant increase in the prevalence of the polymorphic T allele in group 2 patients (severe pain). The polymorphic allele was presented on 90.5% of these cases, while it was only in 58.3% of group 1 patients (mild to moderate pain)–(p = 0.03)–OR: 6.78 (IC: 1.06–43.36).Regarding SNP rs1799971, there was a significant increase in the prevalence of the polymorphic G allele in group 1. The polymorphic allele occurred in 75% of mild to moderate pain patients, while it was only in 38.1% of severe pain patients (group 2)—(p = 0.04)—OR:0.2 (IC:0.04–0.99).This study attempted to correlate SNPs to IC/PBS and to pain severity in these patients. Associations were found in three of the 20 tested SNPs. One of them, rs11127292, was associated with the disease itself. Of the other two, rs6311 was associated with the cases with severe pain, and rs1799971 with mild to moderate pain patients.In regard to the IC/PBS patients, the statistically significant finding was an increase in the prevalence of SNP rs11127292 polymorphic T allele. Although none of the subjects had the homozygote polymorphic genotype, 23.5% of the cases presented one copy of the T allele, while no control subject presented the polymorphic allele. Interestingly this allele was associated with the disease but not pain symptom severity in this study.This SNP was previously studied in patients with fibromyalgia. Polymorphism rs11127292 is located at the MYT1L (myelin transcription factor 1-like) gene and was associated with worse symptomatology in fibromyalgia patients . This geBased on this finding, we can suggest that both IC/PBS and FM may have common underlying nociceptive mechanisms. SNP rs11127292 may also be related to pain in FM and IC/PBS subjects independently, since this study revealed a positive association to IC/PBS in non-fibromyalgic females, and literature previously associated this SNP to FM.The literature supports the idea that some genetic variations in serotoninergic pathways may be associated with chronic pain syndrome susceptibility . SNPs inThere is no previous study in the literature associating rs6311 with IC/PBS. However, some data suggest that the prevalence of the polymorphic allele of this SNP is increased in patients with dyspareunia and concomitant body pain, which gives additional support to our findings ,27.These findings suggest that the previously described serotoninergic involvement in chronic pain syndromes may influence pain perception and susceptibility in IC/PBS patients. Future studies with other polymorphisms of serotonergic pathways can confirm this association. In contrast to this finding, the frequency of another polymorphism of the serotonin receptor gene (5HT2AR), rs6313, was also assessed in our study and showed neither a significant difference in prevalence between patients with IC and controls nor a significant difference among patients with IC who presented with more or less pain symptoms.Previous studies correlate SNP rs1799971 with pain, due to its association with opioid consumption and its high prevalence in a wide variety of ethnicities, reaching 10–15% in Caucasians and up to 50% in Asians. SNP rs1799971 is a polymorphism of OPRM1, a gene which encodes a receptor linked to pain susceptibility, as well as sensitivity to opioids, both endogenous and exogenous –30.In the present study, mild to moderate pain IC/PBS patients had a wild-type A allele frequency of 25% and polymorphic G allele frequency of 75%. IC/PBS females with severe pain had a wild-type A allele prevalence of 61.9% and polymorphic G allele prevalence of 38.1%. These data point to a wild-type A allele association to increased pain sensitivity, suggesting a possible protective effect of the polymorphic G allele against pain susceptibility in these patients.Supporting our findings, previous studies showed an association of SNP rs1799971 G polymorphic allele to an increased affinity of opioid receptors to endogen β endorphins. However, this allele is also associated with reduced μ opioid receptor (OPRM1 gene encoded) expression and signaling. Data in the literature suggest that the G polymorphic allele plays a protective role against pain and is associated with a need for higher doses of opioid drugs for pain relief due to the reduced expression and signaling of the μ opioid receptor –30.It is important to emphasize that although some studies suggest an association between SNP rs1799971 G allele and pain protection, in a meta-analysis, this association with pain perception was not significant, leading only to the need for slightly lower opioid drug doses for pain relief in those carrying this polymorphic allele .Genetic trials assessed polymorphisms and mutations of the SCN-9A gene. This gene encodes a voltage-gated sodium channel (Nav1.7) expressed in the peripheral sensory neurons and dorsal root ganglia that have a critical role in pain sensitivity. It is considered that mutations and polymorphisms in the SCN-9A gene may be related to variations in pain perception –33. A siIn this present study, this finding was not corroborated since there was no statistical difference in this SNP both when comparing IC/PBS patients to the controls and when comparing pain sensitivity among the IC/PBS patients.Recently, some studies have used a less restricted definition of IC/PBS, based on the American Urological Association (AUA) guidelines and European Society for the Study of Interstitial Cystitis (ESSIC), allowing a larger and more heterogeneous number of patients to engage in these studies. The association of IC/PBS with chronic pain syndromes is evident and there is an increased assumption of IC/PBS as a chronic systemic pain syndrome focused on the bladder , 34, 35.In this study, we applied the most restrict, specific and objective criteria for the definition of IC/PBS, allowing a group of selected homogeneous females with a lower range of somatic pain, other than that focused on the bladder.In terms of starting an earlier treatment, there was a recent attempt in clinical practice to extend the definition of some chronic pain syndromes, such as FM, IBS, and IC/PBS, which facilitate the diagnosis and increases the prevalence of the associations of these conditions due to overlapping symptoms.Pain is probably the most debilitating symptom of IC/PBS patients worldwide. In this study, all 34 selected patients experienced this symptom, and in most of the cases it was classified as severe pain . It can be inferred that IC can represent a particular chronic pain syndrome phenotype with underlying genomic susceptibilities and variations in common. An additional limiting factor to the study is that although our analysis yielded statistically significant results if these were subjected to multiple-test statistical correction by Bonferroni method, p-value adjusted for the number of SNPs tested in the study would not be significant.Although this study had a relatively small sample size, we demonstrated the genetic variation in IC/PBS females, however, the differences in SNP expressions might result from the heterogeneity of this syndrome. A clear understanding of genetics along with the polymorphisms that may be related to IC/PBS pathophysiology and that may influence pain susceptibility can help elucidate this syndrome and provide a promising contribution to its diagnosis and management.SNP rs11127292 was more prevalent in the IC/PBS group than in the control group (p = 0.01).The SNP rs6311 polymorphic allele was more prevalent in the severe pain IC/PBS group, and the SNP rs1799971 polymorphic allele was more prevalent in patients with mild to moderate pain.Results must be cautiously considered. Although patients were meticulously selected based on rigid research criteria (NIDDK), IC/PBS is still considered a rare condition, with a difficult diagnosis and heterogeneous phenotypes, which result in a limited sample size, particularly when genetics and polymorphism analysis are concerned. This relatively small sample size may be responsible for the lack of statistically significant associations. Genetic composition can vary with the studied population. This study was conducted in a nationwide referral center of IC/BPS but limited to females and a single country with a heterogeneous genetic profile in the population. Further analyses, including more patients and studies with different ethnic populations, are required to corroborate the relevance of these associations.Subjects in both groups provided written informed consent to participate the study and allowed their biological samples to be genetically analyzed. Approval for the study was given by the Institutional Board of Ethics (CAPPesq–Comissão de Ética para Análise de Projetos de Pesquisa) under the number 796/015.S1 Table(DOCX)Click here for additional data file.


Spine surgery is associated with considerable postoperative pain and can be challenging to treat. A loco-regional technique suitable for spine surgery should cover the dorsal root of the spinal nerves at the levels where surgery is performed. The erector spinae block is a loco-regional technique with promising results and was recently described at the thoracic level. There are no randomized trials of this technique on a lumbar level. This study tests the hypothesis that the 24-h postoperative morphine consumption is significantly lower in patients undergoing posterior lumbar inter-body fusion surgery with a lumbar erector spinae (LUMBES) block when compared with a sham block.This prospective randomized double-blind multicenter study will randomly allocate 80 adult patients undergoing elective posterior lumbar inter-body fusion surgery during general anesthesia to one of two groups as follows: (1) bilateral erector spinae block (20 mL 0.25% levobupivacaine) or (2) bilateral sham block (20 mL NaCl 0.9%). Our primary endpoint is 24-h postoperative morphine consumption. Secondary endpoints include 72-h morphine consumption, intraoperative sufentanil dosage, postoperative pain scores at regular time intervals both at rest and during movement, time to first postoperative mobilization, and the Quality of Recovery 40 survey score.The LUMBES trial is a pragmatic clinical study that will provide evidence of whether a bilateral lumbar erector spinae block is effective in reducing 24-h postoperative morphine consumption in patients undergoing lumbar inter-body fusion surgery. If this hypothesis is confirmed, this finding could contribute to more widespread implementation of this technique.NCT03825198. Registered on 31 Jan 2019.Local ethics committee B300201837508, ClinicalTrials.gov identifier: The online version of this article (10.1186/s13063-019-3541-y) contains supplementary material, which is available to authorized users. Patients undergoing spine surgery often fear postoperative pain, which can be a source of considerable preoperative distress. In many of these patients, so-called chronic pain, requiring high doses of narcotics and other analgesics, has already been diagnosed. In spine surgery, postoperative pain can often be severe and difficult to treat, certainly if a one-dimensional approach is used to achieve pain control , 2. ManyA loco-regional technique suitable for back surgery should cover the innervation of the relevant vertebrae and paravertebral muscles and include the dorsal roots of the spinal nerves at this level . Dorsal Recently, a series of case reports has been described in which bilateral block of the lumbar dorsal ramus nerve resulted in a positive effect on pain scores and morphine consumption after spine surgery . HoweverTheoretically, an infiltration between the erector spinae muscle and the transverse process provides anesthesia of the dorsal ramus at the same vertebral level. Since the local anesthetic is injected into a plane, the solution can spread both caudally and cranially via the thoracolumbar fascia, resulting in anesthesia of the dorsal ramus of the spinal nerves above and below the injected level. The ESB has been described at the thoracic level with promising results. We performed a small feasibility trial in which we found that the ESB could easily be performed without major inconvenience for the patients . In this proposed trial, we aim to determine the effect of a lumbar ESB on pain after back surgery, expressed as morphine consumption during the first 24 h postoperatively.In this prospective, randomized, double-blind placebo-controlled clinical trial, we will investigate the effect of bilateral ESB (20 mL of levobupivacaine 0.25%) on 24-h postoperative morphine consumption when compared with a sham block (20 mL of NaCl 0.9%) following posterior lumbar inter-body fusion surgery. Secondary objectives include the effect of the ESB on the numeric rating scale (NRS) pain scores in rest at fixed time points: at the time of inclusion, in the post-anesthesia care unit (PACU) , and on the ward (twice daily: morning and evening until postoperative day 3). Other secondary objectives are the effect of an ESB on the NRS pain scores during defined movement (mobilization to chair) at 24 h, 48 h, and 72 h; time to first mobilization to chair (hours); time to first walk of 20 m (hours); the required sufentanil dose during surgery (micrograms), total morphine consumption during the first 72 h postoperatively (milligrams), and the Quality of Recovery 40 survey (QoR-40) score at days 1 and 3.https://www.clinicaltrials.gov (reference: NCT03825198) and will be monitored by the clinical trial center of Antwerp University Hospital. Figure This is an investigator-initiated prospective randomized double-blind multicenter trial. The study is being performed in accordance with the Declaration of Helsinki  and Good Clinical Practice (GCP) guidelines. The study has been approved by the ethics committee at Antwerp University Hospital, Wilrijk, Belgium, and AZ Klina Hospital, Brasschaat, Belgium (reference: B300201837508). The trial has been prospectively registered at Patients scheduled for elective 1 or 2 level posterior lumbar inter-body fusion surgery in AZ Klina Hospital and Antwerp University Hospital will be asked for informed consent by a member of the anesthesiology department. Recruitment will occur during the preoperative consultation; it opened on July 9 , 2019, and will close when the required number of patients has been reached.Inclusion criteria are as follows: (1) American Society of Anesthesiologists (ASA) physical status of 1–3, (2) age of 18–75 years, and (3) normal liver and renal function.Exclusion criteria are as follows: (1) body mass index (BMI) of less than 20 or BMI of more than 35; (2) allergy to one or more medications used in the study, including epinephrine, levobupivacaine, dexamethasone, propofol, sufentanil, rocuronium, ketorolac, morphine, ketamine, dehydrobenzperidol, ondansetron, and alizapride; (3) chronic strong opioid use (>3 administrations per week); (4) contraindications to a regional anesthetic technique; and (5) patient refusal or no informed consent or both.Patients will be assigned consecutive numbers upon inclusion in the study. These numbers are randomly allocated (1:1) to the ESB or the sham group by using a web-based randomization system, QMinim. QMinim uses stratified randomization, and stratification will be carried out according to site, gender, and levels of surgery. In QMinim, a minimization procedure is used to randomly assign the patients to ensure a similar distribution of the stratifying arms. Online randomization will be carried out by an independent anesthetist who will also prepare the medication.The ESB study medication will be 20 mL of levobupivacaine 0.25% . The sham group received 20 mL of NaCl 0.9% .All investigators, staff, and patients will be blinded to the treatment groups. The study medication will be prepared by an anesthesiologist who is not involved in the study or in the care of the patient. Both solutions and syringes will appear identical. Unless medically indicated, unmasking will occur only after statistical analysis has been completed.All patients will receive a bilateral ESB. The blocks will be performed by experts in the field of ultrasound-guided regional anesthesia. The blocks will be performed preoperatively in a separate block room with ultrasound after obtaining intravenous (IV) access and application of standard ASA monitoring. The blocks will be placed as described by Chin et al.  and modiThen general anesthesia—propofol 2–3 mg/kg, sufentanil 15 μg, and rocuronium 0.5 mg/kg—will be induced in a standardized way. After tracheal intubation, anesthesia will be maintained with sevoflurane and intraoperative analgesia provided with sufentanil. The dosages of these agents will be determined at the discretion of the attending anesthesiologist. At the end of surgery, patients will receive acetaminophen 1 g IV, ketorolac 0.5 mg/kg IV (maximum of 30 mg), and a morphine loading dose (0.1 mg/kg) IV to manage postoperative pain. Patients will be extubated in the operating theatre and admitted to the PACU. Postoperative nausea and vomiting prophylaxis will be administered with dexamethasone 5 mg IV just before induction of general anesthesia. This will be supplemented, if necessary, by ondansetron 4 mg IV and further with alizapride 50 mg IV as rescue.Postoperative pain in the PACU and on the ward will be treated with regular doses of acetaminophen 1 g IV around the clock (four times daily) and by a patient-controlled intravenous analgesia (PCIA) pump containing morphine at a concentration of 1 mg/mL and dehydrobenzperidol 0.05 mg/mL. The PCIA pump will be programmed as follows: no continuous infusion, a bolus dose of 1.5-mg morphine, a lockout interval of 8 min, and an hourly limit of 7.5 mg. If pain management on the PACU is inadequate, defined as an NRS pain score of more than 3 (0 [no pain] to 10 [worst imaginable pain]), additional boluses of 1-mg morphine IV will be administered by the PACU nurses with a total additional dose of morphine limited to 0.15 mg/kg. If pain management with morphine remains inadequate, an IV ketamine  bolus (0.2 mg/kg) will be administered.The primary endpoint is the morphine consumption during the first 24 h postoperatively in milligrams and will be determined from the PCIA pump.As secondary endpoint, the total morphine consumption in milligrams, during the first 72 postoperative hours, will be extracted out of the PCIA pump. Pain scores at rest will be assessed with the NRS score  and tested at regular time intervals: at the time of inclusion, in the PACU , and on the ward (twice daily: morning and evening until postoperative day 3). Pain scores during defined movement (first moving to a chair and sitting upright) will be registered. Time to first mobilization to a chair (in hours since T0) and time to first walk of 20 m (in hours since T0) will be noted in the patients’ study diary. The QoR-40 score will be calculated from the responses to a standard questionnaire at postoperative days 1 and 3. The QoR-40 is a widely used and extensively validated measure of quality of recovery. It is a 40-item questionnaire on quality of recovery from anesthesia that has been shown to measure health status after surgery , 10.Other endpoints include preoperative expected NRS pain score, postoperative nausea and vomiting score according to hospital protocol, number of administered postoperative anti-emetics, time to first meal, and time to first defecation. All block complications or adverse events will be registered.Discomfort during punctureAllergy for the disinfectant or levobupivacaine Infection at the skin, needle trajectory, or point of injection (very rare). The clinical presentation can be variable . Therefore, the ESB will be performed under strict sterile conditions with a sterile gown, gloves and mask, and a sterile field.Bleeding: very rare with the use of an ultrasound-guided technique. When bleeding occurs, this will be noted by the surgeon.Neural damage: very rare since the target of the puncture is a muscular plane and not the nerve root or nerve ramus itselfLocal anesthetic systemic toxicity: since the doses are substantial, there is a clinically significant risk for local anesthetic systemic toxicity, as with any existing plane block. It can immediately be treated with intralipid. For this reason, the patient will be monitored during and after the placement of the ESB until the start of surgery. Intralipid should be available in any medical environment where regional anesthesia is performed.The ESB is a plane block where a substantial dose of local anesthetic is used. As this technique has only recently been described, limited evidence regarding the potential risks of the block is available. The potential risks described below relate to the known risks of a plane block, facet infiltration, and intramuscular injection:Patients’ demographic data will be collected at the inclusion assessment . The attending anesthesiologist will collect data with regard to the anesthesia and surgical procedure. Nurses will collect the data in the PACU. When the patient is transferred to the orthopedic ward, the Acute Pain Service Team will score the QoR-40 on postoperative days 1 and 3, adjust analgesia when necessary, and systematically screen for side effects. Ward nurses will assess NRS pain scores in the morning and evening on postoperative days 1–3. Morphine patient-controlled analgesia (PCA) consumption will be electronically registered by the PCA pump; all other data will be registered by nurses of the PACU, ward pain department, or trial nurses. All medication can be retrieved from the patient data management systems. Complications will be assessed on the day of discharge. During the 72 h of the trial, data will be registered on paper. After termination of the trial (72 h after surgery), the data will be directly registered in the software program Open Clinica.An independent trial monitor from the Clinical Trial Center at Antwerp University Hospital will conduct a follow-up on the GCP performance of the trial in both study locations. All data will be published anonymously.t test. We plan to include 80 patients in total to compensate for potential dropouts and uncertainty in predicting the actual standard deviation.Our sample size calculation is based on data from a randomized controlled trial comparing the effect of systemic infused lidocaine with placebo on the 24-h morphine requirement in posterior lumbar arthrodesis . We consDemographic and other baseline characteristics will be summarized by treatment group. For categorical variables, frequencies and percentages will be reported. Where values are missing, percentages will be calculated for the available cases, and the denominator will be mentioned. Continuous variables will be summarized as mean with standard deviation or median with interquartile range as appropriate.t test or Mann–Whitney U test will be used as appropriate. The following baseline information prior to randomization will be collected: age, sex, BMI, ASA physical status, indication for surgery, preoperative pain (NRS score), and use of analgesics.Comparisons of demographic and baseline characteristics between the treatment groups will be conducted to assess the effectiveness of randomization. For categorical variables, the chi-squared test or Fisher exact test (when numbers are low) will be used. For continuous variables, a t test intention-to-treat population .SPSS software version 21  or 3.3.2 will be used for statistical analysis. The primary endpoint will be analyzed by using an independent samples To evaluate the sensitivity of the results of the primary outcome analysis, a linear regression will be used to model the cumulative morphine consumption during the first 24 h after surgery with treatment as predictor and taking into account possible confounders.A linear mixed model will be used to model the cumulative morphine consumption over time with subject as a random effect. This model allows correction for confounders and adding a random intercept for site. From this model, the difference in morphine consumption at the different time points can be estimated.t test if they are normally distributed or a Mann–Whitney U test if otherwise. We will also fit a linear regression model for these outcomes, which makes it possible to correct for confounders. A linear mixed model will be studied for the continuous outcomes measured over time.To compare the continuous outcomes  at different time points, we will use an independent samples The time to the different events of interest  will be studied in a time-to-event analysis comparing the two treatment arms. We will use a Cox proportional hazard model to adjust for other variables if necessary.The trial results will be submitted to a peer-reviewed journal regardless of the outcome.Posterior spine surgery ranks among the most painful surgical procedures and can be challenging to treat. High doses of opioids are often prescribed , 2. MuscThis study will provide clinical evidence on the efficacy of the lumbar ESB in reducing postoperative opioid consumption for posterior lumbar inter-body fusion surgery. If the lumbar erector spinae block (LUMBES) trial demonstrates efficacy, the findings will provide high-quality evidence to support the implementation of this technique in clinical practice. Furthermore, it might trigger studies from other researchers to test our outcomes in their practice.Potential benefits of the lumbar ESB include the ease of performance with clear landmarks for ultrasound anatomy. The technique is inherently safe, as the target site for injection is a muscular plane and there is practically no risk for mechanical nerve contact. Other benefits include the possible reduction in perioperative opioid consumption. The ESB is performed in patients under anticoagulant therapy or with coagulopathies . FurtherPossible risks consist primarily of local anesthetic systemic toxicity. Since substantial doses are considered necessary, there is a clinically significant risk for local anesthetic systemic toxicity, as with any high-volume fascial block. For this reason, patients need to be monitored according to American Society of Regional Anesthesia guidelines with Intralipid available at all times .This document is based on version 8  of the original protocol. We anticipate randomly assigning the first patient on July 9, 2019, and plan to complete the study in February 2020.Additional file 1:SPIRIT  2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*. (DOC 125 kb)


Lower back pain is one of the leading causes of disability in the world. The aim of this study was to evaluate the effect of supplementation of dexmedetomidine and neostigmine with lidocaine 1.5% and triamcinolone for epidural block in increasing the duration of analgesia among patients suffering from chronic low back pain. In this double-blind, randomized clinical trial, 33 patients with chronic low back pain were included in three groups of 11 patients for epidural blockage. Triamcinolone (40 mg/ml) was added to lidocaine 1.5% solution (2 cc/segment) for all three groups. In group N, neostigmine was used at a dose of 1 mg (mg), followed by group D (dexmedetomidine 35 μg [0.5 μg/kg]), and grou [ND , but no significant difference was found between the two groups that received dexmedetomidine and a combination of dexmedetomidine + neostigmine. Three months after the injections, there was a significant difference in pain scores between the two groups (P = 0.01). Both neostigmine and dexmedetomidine were capable of reducing the pain of patients with chronic low back pain after epidural block. However, neostigmine’s impact is lower compared to dexmedetomidine. The combination of the two drugs also reduced the pain scores of the patients after the intervention. Over the past two decades, extensive epidemiological studies have been carried out on low back pain and indicate high prevalence and high direct and indirect costs in areas such as medical, legal, employment (absenteeism), products, and inadequate quality of life , 2. MoreAccording to estimates, approximately 1% to 2% of the active population in the United States suffers from severe disability due to back pain, and 12% to 15% of annual visits of patients in American healthcare centers have been attributed to back pain. 12% to 15% of annual visits to patients in American health care centers due to low back pain. In Iran, back pain is one of the issues that is common in the society, with high prevalence among high school students (17%), nurses (62%) and pregnant women 84%) , 4. The % , 4. ThIn this way, the strength and mechanics of the patient’s body improve, physical stress will be minimized, and pain will be resolved for a longer period  Among thDespite extensive research in this area, there is still controversy over the number of epidural infusions and their maximum frequency, and the administration route of the epidural injection . In addition, the researchers still failed to reach agreement on the ideal volume of consumed drugs, injections or non-injections of corticosteroids, drug alternatives as to the main epidural anesthetic drug, adjuvant drugs and the effectiveness of these methods in reducing patient’s pain -12. DiffOther adjuvant drugs include dexmedetomidine, which is a highly sensitive and highly selective α-2 adrenergic receptor agonist with a tendency of more than 8-fold in comparison with clonidine, thus reducing undesired side effects of alpha-1 receptors , 17. VarThis study was a double-blind, randomized clinical trial on all patients with chronic low back pain who were considered an epidural block candidate at the Amiralmomenin Hospital and Vali Asr Hospital in Arak, Iran.1. All patients with chronic low back pain who were candidates for the lumbar epidural block. 2. All patients with the intent to participate in the study. 3. Patients aged 30-70 years 4. Patients with physical status ASA I or II. 5. Absence of vitamin D deficiency.1. Patients outside the age range of 30-70 years 2. Patients who were not candidates for an epidural block. 3. Patients with hypersensitivity to lidocaine neostigmine and dexmedetomidine. 4. Patients with physical status ASA greater than II . 5. Patients with failed epidural blocks. 6. Female patients who are pregnant or lactating. 7. Patients with a history of fracture. 8. Patients who are suffering from uncontrolled psychological disorders.In this study, all patients with chronic low back pain (back pain for more than 6 weeks), candidates for epidural block with physical status ASA I or II, who have never had an allergic reaction to local anesthetics and epidural anesthesia were randomly divided into three groups: N (Neostigmine), D (Dexmedetomidine), and ND (Neostigmine and Dexmedetomidine). Patients who met the inclusion criteria and provided written informed consent were included in the study. At first, the Ringer solution of 5 cc/kg was injected 10 to 15 minutes before the epidural block for adequate hydration for each patient of the three groups. Afterward, the patients were placed in a sitting position, and the subjects received epidural blocks at the L4-L5 or L5-S1 level using the interlaminar approach using a 19- or 20-gauge epidural catheter. After entering the epidural space and confirming the correctness of needle placement, the drug combination was injected. In all three groups, 2 cc/segment of triamcinolone (40 mg/ml) was added to the lidocaine 1.5% solution, followed by injection.In group N, neostigmine was used at a dose of 1 mg (mg), followed by group D (dexmedetomidine 35 μg [0.5 μg/kg]) and group ND , PR (pulse rate) and NIBP (non-invasive blood pressure) were monitored. Ultimately, after performing the procedure and ensuring that the hemodynamic status of the patient was stable, they were transferred to the recovery room. Complete monitoring  was continued even after the patients were transferred to the recovery room.This double-blind study included patients who provided written informed consent, the injectable solution composition being unknown. Furthermore, the healthcare professional responsible for completing the questionnaires and recording the pain and disability scores, was not aware of the patients in the studied groups and did not know about the epidural block, only completing questionnaires based on the numbers assigned in the operating room by an anesthesiologist responsible for the study (who performed the procedure).A total of 33 patients with chronic low back pain who met the inclusion criteria were randomly assigned to three groups  using a randomized table. Therefore, 11 patients were assigned to each group.The pain score and duration of analgesia were evaluated based on the visual analogue scale (VAS) in the recovery room, one month and three months after the procedure. Improvement of performance was also evaluated based on the score of disability (ODI - Oswestry Disability Index) before and one month after the intervention. The duration of analgesia was recorded on the basis of a painkiller request (in terms of days); therefore, all patients were requested to return to the clinic or address to a pain management clinic if the pain would return. The exact duration of analgesia was recorded in the questionnaires to track the patients’ pain. Also, other patient information, including demographic data, hemodynamic status  during the procedure and recovery, as well as the mean time needed for movement onset were recorded by questionnaires.According to the type of study , 33 patients who met the inclusion criteria and provided written informed consent, were randomly assigned to three equal groups: N (neostigmine), D (dexmedetomidine) and DN (dexmedetomidine and neostigmine).In this study, SPSS 19 software was used to analyze questionnaires data. Statistical analysis was performed using T-test and ANOVA. Finally, the results were shown in Tables and graphs.In this study, the names and characteristics of the subjects were confidential and costs were not imposed on the patient’s family and hospital. In addition, completion of the form and the patients were satisfied after receiving training providing written consent. At all stages of the research, such as drafting the proposal, collecting samples and analyzing data, the researchers were required to respect the ethical provisions issued by the Ministry of Health and the Helsinki Declaration. This research was approved by the Ethics Committee of the Arak Medical University Research Council (IR.ARAKMU.REC.1395.256).A total of 11 patients were enrolled in each group; the mean age and distribution of the sexual abnormalities of these patients are listed in Based on As indicated in Nevertheless, pain scores were significantly different at three months after the injection; the pain scores in the neostigmine group were higher than the other two groups (p = 0.01), but no significant difference was revealed between the dexmedetomidine and combined group (dexmedetomidine + neostigmine).As According to Our findings showed no significant difference between the three groups in terms of ODI scoring before the intervention; almost all ODI scores were the same in all three groups . However, the ODI score was significantly higher in the neostigmine group after the intervention when compared with the other two groups (P = 0.02), but no significant difference was found between the two groups and the combined group .As shown in Achieving an appropriate combination to increase the duration of analgesia in patients with chronic low back pain is one of the specific goals of anesthetics and pain management specialists. In our study, the comparison of the addition of dexmedetomidine and neostigmine to lidocaine 1.5% and triamcinolone for epidural block in patients suffering from chronic low back pain were studied. The results indicated that pain scores of patients of all three groups in the recovery room had dropped dramatically, but did not show any significant difference. However, pain scores were significantly different at one and three months after the intervention. Specifically, the pain scores in the dexmedetomidine group (D) and the combined group (D + N) were significantly lower than the neostigmine (N) group, but there were no differences between the dexmedetomidine and combined group).The mean time needed for movement onset of patients was the same for all three groups, and analgesia duration was not significantly different among the three groups within 24 hours after the intervention. Comparison of the ODI scores in the three groups revealed that the scores were significantly reduced at one-month after the intervention in the dexmedetomidine and combined group compared to the neostigmine group. However, there was no significant difference between the dexmedetomidine and the combined group.Our results are consistent with the previous studies. Nourmohammadpour et al. conducted a study in 2016 on 7889 Iranian patients aged 30-70 years with neck pain, back pain, and chronic knee pain. The prevalence rates of chronic neck pain, chronic low back pain, and chronic knee pain were 15.3%, 27.18 % and 29.97%, respectively. In the aforementioned study, in addition to identifying the risk factors for chronic low back pain and neck pain, the use of regional blocks has been recommended to reduce chronic pain in cases of chronic low back pain and neck pain. In our study, epidural block was capable of significantly reducing the pain of patients with chronic low back pain, which was consistent with the results of the above-mentioned study .In another study conducted by Ackerma et al. in 2007, 90 patients aged 18-60 years with L5-S1 disc and chronic low back pain were evaluated. It has been determined that epidural injection using a caudal, intraluminal, and trans-foraminal approach have been effective in the chronic pain of the patients included in the study. Other results of the study mentioned above indicated that trans-foraminal epidural steroid injections were more effective compared to the caudal and intraluminal approach [In another study, the effect of lumbar epidural block on patients with chronic low back pain has been investigated, where patients were divided into two groups: local anesthetic alone and local anesthetic in combination with betamethasone. The second group (combined group) showed a significant reduction in the ODI and pain scores compared to the first group . The ODI score was found to be significantly reduced in 69% of patients of the first group and 83% of patients of the second group. Therefore, epidural injections of steroids together with local anesthetics have been shown to be effective in reducing chronic back pain .These results were consistent with our findings; although all of the three local anesthetics and steroid anesthetics were administered epidurally in our study, the ODI and pain scores were reduced in our patients.In 2015, Chou et al. discussed pain management injection therapies for patients suffering from low back pain, where epidural steroid injections for preventing the pain caused by chronic radiculopathies led to an immediate improvement in the function and reduced the pain of the patients.However, the benefits of these injections were short and unstable and did not affect the need for long-term surgical care . The epiComparison of our study with prior research reports showed that our results were consistent with most of the previous studies. In our study, as in most previous studies, the injection of local and steroid anesthetics has led to a reduction in the chronic pain of the patients. Moreover, the addition of two adjuvants (neostigmine and dexmedetomidine) has led to a reduction in the pain and ODI scores. Regarding the use of both dexmedetomidine and neostigmine in the present study and their appropriate effects as an adjuvant along with local anesthetics and steroids, the final effect of these two adjuvants was compared to eventually provide an appropriate combination for increasing the duration of analgesia.After epidural block, both neostigmine and dexmedetomidine, along with local anesthetics and steroids, were capable of reducing the pain of patients suffering from chronic low back pain. Neostigmine has a lower effect on pain when compared to dexmedetomidine. Furthermore, the combination of the two drugs also reduced the pain scores of the patients after the intervention, although this reduction was not significant in comparison with the dexmedetomidine group.We are grateful to the Clinical Research Center of Valiasr Hospital, the operative’s operating room for Valiasr Hospital and the surgical team of Amir Al-Momenin Hospital.The authors confirm that there are no conflicts of interest.


The patient satisfaction of symptoms improvement and disease factors that may affect long-term treatment efficacy of radiofrequency ablation (RFA) for non-functioning solid benign thyroid nodules (TNs) over a 2-year follow up study was investigated.This retrospective study evaluated 194 non-functioning solid benign TNs of 103 patients. The TNs were categorized as small (≤5 ml), medium (5.1 to 13 ml), intermediate (13.1 to 30 ml) and large (over 30 ml) according to the initial volume of TNs before ablation. Clinical evaluation and contrast-enhanced ultrasound (CEUS) were carried out before ablation and the follow up at 1, 3, 6 months and every 6 months after ablation. All patients were asked to assess the cosmetic score (1–4 scores) and symptom score (0–10 scores) before ablation and every follow up after ablation.P < 0.001). The small group of nodules shrunk larger compared to the medium, intermediate and large groups (P < 0.001). Cosmetic signs and pressure symptoms were significantly improved, particularly in the intermediate and large groups (P < 0.05).All patients underwent RFA without any major complications. The mean treatment sessions were 1.5 ± 0.6. 98 nodules required a single session , 87 required two sessions , 9 required three sessions . The average follow up months were 16.3 ± 5.6  and no nodule regrew in our study. After RFA treatment, the TNs volume significantly decreased (RFA is effective for treating non-functioning solid benign TNs and controlling clinical symptoms with a low complication rate during 2 years follow up. The reduction rate was related to the initial volume of nodules. Patients were satisfied with cosmetic signs and pressure symptoms improvement, particularly in the intermediate and large groups. However, multiple RFA treatments should be used in larger nodules to achieve the desired clinical outcomes. The incidence of thyroid nodules (TNs) is fairly high, with the development of medical imaging technologies the presence of thyroid nodule increases up to 40–50% , 2. SomeRadiofrequency ablation (RFA) has been successfully applied in treating liver tumors . BecauseAll patients were required to sign informed consents before contrast-enhanced ultrasound (CEUS), CNB and RFA. This retrospective study was approved by the Beijing Tian Tan Hospital Ethics Committee and the Chinese PLA General Hospital Ethics Committee. From June 2014 to July 2015, 412 TNs of 270 patients received RFA for treating TNs in Beijing Tian Tan Hospital and Chinese PLA General Hospital. Patients enrolled in this study were based on the following criteria: (a) pathological diagnosis was benign by ultrasound guided CNB of thyroid nodule; (b) TNs with solid portion over 80%; (c) thyroid stimulating hormone (TSH), anti-thyroid antibodies and free T3/T4 within the normal range; (d) patients with normal electrocardiogram (ECG) and chest X-ray; (e) patients reported foreign body sensation, compression symptom and local uplift affection due to large volume of nodules, and worries of nodules growing rapidly or malignant lesions; (f) refusal or ineligible for surgery; (g) patients voluntarily receive RFA after being informed of the treatment features of RFA. Exclusion criteria were: (a) the distance from TNs to trachea-esophageal groove is less than 5 mm; (b) pathological diagnosis was malignant by ultrasound guided CNB; (c) patients with contra-lateral vocal cord paralysis; (d) patients diagnosed with serious disease that can’t tolerate RFA; (e) Pregnancy. Finally, 103 patients with a total of 194 TNs  were enrolled in this study and more than 2 years follow up was conducted. At the enrollment, all patients were asked to assess the cosmetic score (1–4 scores)  and rate symptom score (0–10 scores) on a 10 cm visual analog scale , 18.The equation of volume of thyroid nodule was V = abcπ/6,  . TNs werAfter ablation, patients were followed up at 1, 3, 6, 12 and every 6 months thereafter. Symptom and cosmetic scores and complications of RFA were evaluated at each follow up. CEUS was used to evaluate for recurrence and detect the volume of ablation. Volume reduction ratio (VRR) was calculated by the following equation: VRR = [Initial Volume (ml) – Final Volume (ml)]/Initial Volume (ml) × 100% . RegrowtP value less than 0.05 indicated there was significant statistical difference.SPSS 17.0 software was used to perform statistical analysis. Changes in VRR, symptom and cosmetic scores between every two follow up periods were compared by Wilcoxon signed rank tests. RFA was applied in 194 TNs of 103 patients in this study, 36 male and 67 female. The average age was 47.6 ± 11.3 years . TNs were situated at left lobe, right lobe and isthmus in 81, 103 and 10 cases, respectively. The mean initial volume of TNs was 21.2 ± 19.7 ml . Table It was possible to successfully perform the RFA in all cases as planned. Power of 3 W was used in 21 nodules; 5 W – 6 W was used in 119 nodules; 7 W – 8 W was used in 54 nodules. No immediate or later major complications occurred during and after RFA. Mild to moderate local pain occurred during RFA in 12 patients  and lasted for 1 to 3 days and alleviated with analgesics. The average sessions of RFA treatment were 1.5 ± 0.6. 98 nodules required a single session ; 87 required two sessions ; 9 required three sessions .P < 0.001). During the follow up period, CEUS showed no nodule regrew (regrowth is defined as the nodule volume increased 50% more than the previous examination). 39 nodules completely disappeared . 27 nodules were in small group  and 12 nodules were in medium group  at the last follow up visit. Figures The average follow up months were 16.3 ± 5.6 range, 6–24 months) in this study. The VRR at each follow up after RFA in the four groups of nodules are shown in Table 4 months P < 0.05), while no improvement in the small and medium groups. Cosmetic score significantly improved in all groups (P < 0.05).Patients achieved a significant decrease in the cosmetic and symptom scores between baseline and the last follow up Table . SymptomTraditional treatments for symptomatic TNs include surgery and medication. Surgical options  can not only be invasive but also cause pain and cosmetic defects in patients. In addition, postsurgical long-term administration of thyroid hormone therapy is usually needed. Therefore, minimally invasive procedures such as endoscopic thyroid surgeries and levothyroxine therapy provide an alternative treatment method of TNs . HoweverIn recent years, thermal ablation therapies have been introduced for treating benign TNs such as microwaves, laser and radiofrequency ablation , 24. HowThis 2 years retrospective study demonstrated that RFA was effective for treating non-functioning solid benign TNs and controlling clinical symptoms. The factor affecting treatment effect was initial volume of TNs. The VRR of the small group of nodules were larger compared to the medium, intermediate and large groups. To prevent the regrowth of nodules, we applied the moving shot technique to complete ablation of the nodules in this study. However, larger nodules required multiple RFA sessions to achieve similar VRR than smaller nodules. No nodule regrew with regrowth defined as the nodule volume increased 50% more than the previous examination. Cosmetic and pressure symptoms are significantly improved in particular intermediate and large nodules.Regarding safety, this study showed no major complications and a low complication rate. No perinodular hematoma, nerve injury, local infection, skin burn or hypothyroidism was found, and only 12 patients  had a mild local pain during RFA and lasted for 1 to 3 days, which alleviated with analgesics. The low power and prolonged time of RFA in this study might result in the low complication rate.No comparison with surgery or other treatment methods is the limitation of this retrospective study.This 2 years follow up study has shown that RFA was effective for treating non-functioning solid benign TNs with a low complication rate as well as in controlling the problems caused by TNs. The reduction rate was related to the initial volume of nodules. The best reduction rate was observed in the small group of nodules. However, multiple RFA treatments should be used in larger nodules to achieve the desired clinical outcomes. Cosmetic signs and pressure symptoms were improved significantly, particularly in the intermediate and large groups. Therefore, RFA may be used in clinical practice as a minimally invasive method for treating non-functioning solid benign TNs.