Pain management after coronary artery bypass graft (CABG) surgery remains challenging.This study aimed to compare the effects of Ketorolac and Paracetamol on postoperative CABG pain relief.This double-blind randomized clinical trial study was conducted in Ahvaz, Iran, from September 2018–December 2019. Two consecutive groups of 60 patients undergoing elective on-pump coronary artery bypass graft surgery.. Primary outcomes were: visual analog pain scale (VAS) at the time point immediately after extubation (baseline) and at 6, 12, 24 and 48 h and the total dose of morphine consumption. Secondary outcomes included the hemodynamic variables, weaning time, chest tube derange, in-hospital mortality and myocardial infarction.The patients were divided into 0.5 mg/kg of ketorolac mg/dl and 10 mg/kg of Paracetamol after surgery for pain management: The data were analyzed using SPSS version 22. The Mann-Whitney U-test was used to compare demographic data, VAS scores, vital signs, and side effects. Repeated measurements were tested within groups using Friedman’s ANOVA and the Wilcoxon rank-sum test. Values were expressed as means ± standard deviations. Statistical significance was defined as a p-value < 0.05.Statistical analysisCompared with baseline scores, there were significant declines in VAS scores in both groups throughout the time sequence (P< 0.05). The statistical VAS score was slightly higher in the Paracetamol group at most time points, except for the time of 6 h. However, at 24 and 48 h, the VAS score in group Paracetamol was significantly higher than in group Ketorolac. There were no significant differences between groups about hemodynamic variables.The efficacy of ketorolac is comparable to that of Paracetamol in postoperative CABG pain relief.IRCT20150216021098N5. Registered at 2019-09-12. Control of pain management after coronary artery bypass graft (CABG) surgery remains challenging. Incompetently controlled postoperative pain can increase catecholamine levels, triggering myocardial ischemia, stroke, and bleeding complications. Limiting patient mobility, poorly managed postoperative pain can increase the risk of deep vein thrombosis and pneumonia, in addition to harmful psychological consequences such as insomnia and demoralization , 2. PostParacetamol is usually considered to be a frail inhibitor of the synthesis of prostaglandins (PGs). However, the in vivo effects of Paracetamol are alike to those of the discerning cyclooxygenase-2 (COX-2) inhibitors. It is the most commonly suggested pain-relieving for the treatment of acute pain . Its benKetorolac has been used for postoperative analgesia in combination with opioids. Several studies have reported that ketorolac is as effective as morphine or meperidine for analgesia after some types of surgical procedures . HoweverThis double-blind randomized clinical trial study was conducted in Golestan Hospital, Ahvaz, Iran, from September 2018–December 2019 with Ethics code: IR.AJUMS.REC.1398.050 from Anesthesiology and Pain Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran, and Trial registration number: IRCT20150216021098N5.Sixty patients undergoing elective on-pump coronary artery bypass graft surgery. After clearly explaining the objective and potential risks and benefits of the study, a written consent form for participation in the study was obtained from all patients.Aged 30–70 years, ASA III, Both of sex, Ejection Fraction≥30%, undergoing elective CABG.Severe hepatic and renal disease, consumption of anti-inflammatory drugs or antipyretic drugs before the study, redo surgery, history of cerebrovascular accident (CVA), and thrombocytopenia.Randomization: randomization was performed using computer-generated random digits to ensure that patients and investigators were blind to the treatment assignment before study entry, and the allocation was done 1:1 to receive either ketorolac or Paracetamol. Randomization was not performed until electronically confirming the eligibility criteria in the web-based case report form. Randomization was performed centrally without stratification. The sequence was generated by an independent statistician using a random number generator with a 1:1 allocation using random block sizes of 2. In this study patients and researchers were blinded.The sample size of this study was calculated using the sample size estimation formula. The 95% confidence interval (CI) level was considered. The study population consisted of 90 patients. Based on the previous data . After iAfter arrival to the operation room, standard monitoring included five-lead electrocardiography, pulse oximetry and arterial line for continuous blood pressure monitoring and blood gases were inserted. A standard anesthesia technique was used for all patients. The anesthetic drug doses were calculated according to body weight; midazolam at 0.1 mg/kg was given as IV premedication. Induction of anesthesia was induced fentanyl 15 μg/kg, propofol 1 mg/kg, and pancuronium 0.1–0.15 mg/kg). Anesthesia was maintained with a continues infusion of propofol 1–1.5 mg/kg/h, fentanyl 4 μg/kg/h, 0.25 mg/kg/h midazolam, and 0.3 mg/kg/h cisatracurium until the end of surgery. Isoflurane supplementation was used at the discretion of the attending anesthesiologist. After induction of general anesthesia, a central venous catheter was introduced. For initiation of cardiopulmonary bypass, 350 u/kg heparin was injected to all patients. Heparin dosage was attuned based on goal ACT 450–480 s. After the bypass was terminated, protamine 1 mg/kg was given for the reversal of heparin. Cardiac surgery and postoperative management were standardized.After surgery, all the patients were admitted to the cardiovascular ICU, with a standard protocol for sedation, analgesia (propofol 0.5 mg/kg/h and morphine sulfate 0.1 mg/kg/h), and management of mechanical ventilation (SIMV mode of ventilation).Immediately after the transfer of patients to ICU, the intervention began. The patients in the ketorolac group were administered at a rate of 0.5 mg/kg IV admixed with 100 ml of normal saline each 6 h for 24 h. A bolus may be given at the start of therapy if desired. The patients in the Paracetamol group were given 10 mg/kg IV of Paracetamol  for 30 min each 6 h for 24 h.  using a standardized protocol: bolus dose of 2 mg, dose duration of 2 min, lockout interval of 13 min (15 min effective lockout time), and with no background infusion and no upper dose limit. Before commencing the PCA, the nurses in the PACU were allowed to give morphine sulfate 2mgIV before extubation for the treatment of pain if required. Morphine consumption was recorded from the PCA device at the end of the 48-h study period. Per protocol, the primary efficacy variable was cumulative morphine consumption (the combined amount administered via the PCA device and given as rescue doses) at the end of the 48-h postoperative period. If pain relief was insufficient (VAS score > 3 at rest), nurses were allowed to give an extra bolus of morphine2 mg IV as a rescue analgesic once an hour. Renal function test (serum creatinine) were measured the evening before surgery and 72 h after surgery. Bleeding after surgery was measured as chest tube drainage. The number of red cell units transfused was recorded.Primary outcomes were: visual analog pain scale (VAS) at the time point immediately after extubation (baseline) and at 6, 12, 24 and 48 h and the total dose of morphine consumption. Secondary outcomes included the hemodynamic variables, weaning time, postoperative bleeding, myocardial infarction, CVA, TIA, in-hospital mortality and postoperative serum creatinine.Pain intensity levels were subjectively measured using a 10 cm visual analog pain scale . We assessed VAS and hemodynamic variables  of each regimen immediately after extubation (baseline) and at 6, 12, 24, and 48 h.P value ≤0.05 was considered to be statistically significant. All analyses were performed using SPSS for Windows version 22.0 .Numerical variables were reported as mean ± standard deviation (SD). Quantitative and qualitative variables were measured by independent t-test, and ANOVA test respectively. During the study period from September 2018–December 2019, 100 patients undergoing elective on-pump CABG surgery were eligible to participate in the trial. Forty patients did not have inclusion criteria Finally, 60 patients were enrolled in the study and were assigned into two groups of ketorolac and Paracetamol, 30 patients each.   Table .Table 1p = 0.027) and 48 h (0.22 ± 0.15 mg in Paracetamol versus 2.18 ± 0.52 mg in ketorolac group p = 0.007) after extubation  Fig. .Fig. 3PComparison of the two groups receiving ketorolac and Paracetamol showed that there was no significant difference between the two groups in terms of platelet count, bleeding time, and chest tube derange Table p = 0.003). (Table Weaning time significantly lower in the Paracetamol group than the ketorolac group . Table .Table 4P > 0.05) Table Comparison of the two groups receiving ketorolac and Paracetamol showed that there was no significant difference between the two groups in terms of the hospital mortality rate MI, CVA, TIA, and postoperative serum creatinine. Of course, their study was in congenital cardiac patients.NSAIDs block the synthesis of prostaglandins through the inhibition of COX-1 and COX-2, thus lowering the production of acute inflammatory response mediators. By decreasing the inflammatory response to surgical trauma, NSAIDs reduce peripheral nociception. NSAIDs also appear to have a central analgesic mechanism, possibly through the inhibition of prostaglandin synthesis within the spinal cord. In general, NSAIDs have a low side-effect profile when administered for the short-term purpose of perioperative analgesia after cardiac surgery , 22.Ketorolac is effective at reducing pain, and several studies have reported its safety and efficacy in the perioperative period. In many reports, the use of ketorolac as an adjuvant to a PCA opioid resulted in an opioid-sparing effect ranging from 16 to 33% . The hypThe authors previously reported the results of a randomized trial that found that oral naproxen is effective as an adjunct for the optimization of pain control and lung recovery after CABG, without increasing the risk of postoperative complications. In contrast to naproxen, intravenous ketorolac can be provided earlier in the postoperative period before the resumption of oral intake. Ketorolac provides an analgesic effect similar to that of fentanyl, but with a lower incidence of postoperative nausea and somnolence, and leads to an earlier return of bowel function. (15) With these advantages over opioids, ketorolac administration ultimately may shorten hospital length of stay.Paracetamol has been studied in many surgical settings such as functional endoscopic sinus surgery, cholecystectomy, hysterectomy, and orthopedic surgeries with variable favorable results , 28. TheParacetamol has resulted in hypotension in critically ill patients although this effect could be explained as an allergic phenomenon . The remThe hemodynamic effects of NSAIDs used for postoperative pain control in patients undergoing major vascular surgery have been reported in a few studies , 34. AltOur study found no association between the use of 0.5 mg/kg ketorolac and mortality, MI, or clinically important hemorrhage. These results, however, are limited by unexpected differences in the baseline characteristics of the number of on-pump CABG patients and STS risk scores. On-pump CABG means a patient placed on cardiopulmonary bypass throughout surgery . The STSThis study has several limitations. First; the sample size was small second; this study was single-centered. We recommended future trials with a large sample size, multi-center and long duration of follow-up.In conclusion, ketorolac and Paracetamol may be produced marked postoperative pain relief after cardiac surgery. The analgesic effects of these compounds were not associated with a clinically significant impairment in hemodynamic function and mortality, MI, or clinically significant bleeding in postoperative CABG patients. So further study with similarly coordinated groups and the larger sample size is necessary to sufficiently determine the cardiovascular risks associated with administration of IV ketorolac.


This study aimed to predict the quality of life (QOL) in patients with Painful Diabetic Neuropathy (PDN) based on pain severity, pain catastrophizing, pain acceptance, depression, anxiety, and sleep disturbance. Also, this study was aimed to assess the prevalence of psychiatric symptoms in Iranian patients with PDN.1120 patients  participated in the research. Data were collected by the Quality of life questionnaire (NeuroQoL); Beck Depression Inventory, Beck Anxiety Inventory, the visual analog scale for pain severity, Pain Catastrophizing Scale (PCS), Chronic Pain Acceptance Questionnaire (CPAQ) and Pittsburgh Sleep Quality Index (PSQI). Finally, the data were analyzed using SPSS-26 by multiple regression analysis.The results showed the regression models’ significance, and the dependent variables predicted 42% of total changes in the QOL. The most significant predicting factors were depression, pain catastrophizing, pain acceptance, pain severity, sleep disturbance, and anxiety in order. In patients with PDN, the prevalence of sleep disturbances, depression, and anxiety were 85.5%, 68.2%, and 62.1%, respectively. Also, comorbid depression and anxiety were found in 47% of patients.Results demonstrated a significant relationship between pain-related and psychiatric dimensions with QOL. Thus, it is suggested to design more specific psychological-based rehabilitation interventions in which these variables are considered. They should focus on more significant variables (such as depression and pain catastrophizing) to reach better treatment outcomes. Furthermore, this research shows a high level of anxiety, depression, and sleep disturbance in Iranian patients with PDN. Thus, experts and clinicians are suggested to focus on reducing these psychiatric symptoms. Diabetes is known as the silent killer , which oConclusively, problems related to pain, depression, anxiety, and sleep disturbance severely reduce the QoL  in patients with PDN. These symptoms have been investigated in several studies , 12, 18,On the other hand, the prevalence of diabetes is more than 15% in Iran's general population . The preWe conducted a cross-sectional study of patients with painful diabetic neuropathy in Tehran, the Capital of Iran, from November 1, 2019, to August 1, 2020.Inclusion criteria include (1) Willingness to participate in research, (2) ranging in age between 18 and 70, (3) Diagnosed with PDN by a neurologist, (4) No history of hospitalization in psychiatric wards, and (5) No history or current diagnosis of substance abuse. Exclusion criteria include (1) dissatisfaction with entering the research, and (2) Failure to complete the questionnaires.Based on the convenience sampling method, 1500 patients with PDN were selected to participate in this research. Each patient had medical records in one of the specialized diabetes treatment centers in Tehran Province. All of them had received PDN diagnosis and were under treatment. They were contacted and explained about the study. Extensive explanations were given about the study. Then each individual was given an appointment at the clinic to complete the tools of the research. Anonymous paper surveys were utilized for gathering data. After screening based on criteria, an appointment was made for each patient. These evaluations were held by five psychologists separately (to speed up the assessment process). Patients separately answered the questionnaire booklet under the five psychologists' administration and supervision (blinded about research aims). Besides, written informed consent was taken from all patients.Of these 1500 patients, 284 neither went to the center nor responded to the researchers' calls; Forty-eight patients had a history of substance use or were taking it; Fifteen had a history of hospitalization in a psychiatric hospital, reported in psychiatric hospitals or had traumatic brain injury; Thirty-three people answered the questionnaires incompletely or without accuracy. Finally, 1120 people entered the results analysis process. Figure The Neuropathy Specific Quality of life questionnaire (NeuroQoL) is an appropriate validated measure for neuropathic QoL. It has 27 items. NeuroQoL assesses diabetic neuropathy-related emotional and physical problems affecting diurnal life and well-being. NeuroQoL consists six subscales: painful symptoms, dependence on others, emotional distress, unsteadiness while walking or standing, restriction in daily activities, paresthesia, interpersonal problems, and decreased or lack of ability to feel the temperature. NeuroQoL reliably captures the critical aspects of the patients’ experience of PDN and is a valid instrument for examining the impact of neuropathy on QOL . The relThe severity of pain of the subjects was assessed by a 10-cm visual analog scale (VAS) where the "0" means not feeling any pain, and "10" shows unbearable severe pain .Pain Catastrophizing Scale (PCS) was used to assess pain catastrophizing in PDN patients. The PCS is a 13-item self-report scale developed to assess individuals’ rate of catastrophic beliefs related to painful experiences. PCS ranged on a 5-point Likert scale . Higher scores mean greater pain catastrophizing. The PCS has shown good psychometric properties for clinical /non-clinical Iranian samples  , 26.Chronic Pain Acceptance Questionnaire (CPAQ) was used to assess pain acceptance. The CPAQ is a 20 item assessment tool for chronic pain that each subject should answer every item in a 7-point Likert scale. Each item scored on a 7-point Likert scale, ranging from 0 (never) to 6 , and the items for the pain satisfaction scale scored reversely, ranging from 0 to 120. Higher scores indicate higher levels of pain acceptance. The Persian version of the CPAQ also has shown adequate psychometric properties. Assessment of psychometric properties of the Persian version has shown that the value of coefficient was 0.89 and the value of test–retest reliability was 0.71[Second edition of the Beck Depression Inventory (BDI-II) is a 21-item scale for assessing depression. Each item scored on a 4-point Likert scale, ranging from 0 (never) to 3 . The minimum score in this test can be 0, and the maximum can be 63. The cut-off scores of BDI include minimal or nothing depression (0–13), mild depression (14–19), moderate depression 20–28), and severe above 29). In the BDI.II, the cut-off point for adulthood depression in the medical context is 14 .BDI is u, and sev. In the Beck Anxiety Inventory (BAI) is also used for assessing anxiety. BAI is a 21-item scale that is scored on a Likert scale from zero to three. Each item represents one of the most prevalent symptoms of anxiety; the total score ranges from 0 to 63. The Cronbach’s alpha of the English version of BAI has been reported to be 0.82. Researches have demonstrated that the Persian version of BAI has high-grade reliability (r = 0.72), a suitable validity (r = 0.83), and an excellent internal consistency (a = 0.92) . AccordiPittsburgh Sleep Quality Index (PSQI) is used for assessing sleep quality. PSQI contains 18 items related to sleep quality in the past month. The total score ranges from zero (without any sleep disturbance) to 21 (wholly impaired sleep). The value of reliability is 0.83. PSQI has an average sensitivity of 90% and specificity of more than 86% for identifying cases with a sleep disorder, using a cut-off score of five. In the Iranian psychiatrically healthy community, the value of Cronbach’s alpha coefficient is 0.78, and the sensitivity coefficient is more than 0.95..Pearson’s correlation and multiple linear regression models were employed to investigate the relationship between variables. SPSS version 26 statistical package for social sciences was utilized for analyzing data. The Kolmogorov–Smirnov test was applied for normalizing data. Homoscedasticity was examined using the scatter plot. Multiple outliers were evaluated by Mahalanobis distance.Five hundred sixty patients with PDN participated in this study. The mean age of the subjects was 53.6 ± 12.6 years, of which more than half were male  and married (90.9%). Also, the mean duration of their diabetes was 13.3 ± 3.4  between QoL, pain severity, anxiety, depression, pain acceptance, pain catastrophizing, and sleep disturbance are presented in Table According to the Table Normality and homoscedasticity of the error distribution were examined before operating the regression. The Kolmogorov–Smirnov analysis showed that the variables had a normal distribution. Homoscedasticity. In the current data, the residuals and the variance of the residuals were the same for all predicted variables. None of the distances were bigger than or equal to Chi‑square, so there were no multiple outliers among the data.A step‑by‑step multiple regression analysis was conducted to predict life quality (criterion variable) based on pain severity, pain catastrophizing, pain acceptance, depression, anxiety, and sleep disturbance (predictive variables). Six models were implemented in which the sixth one demonstrated the highest R square.According to Table Table With a cut-off point of 14, the prevalence of depressive symptoms was 63.2%. Scores are distributed in the Spectrum of Depression, which are reported in Table As stated in the method section, the cut-off point for clinically significant anxiety on the BAI is 16. The prevalence of anxiety in patients with PDN is 62.1%. Scores are distributed in the Spectrum of anxiety, which are reported in Table Also, regarding the comorbidity between depression and anxiety, 47% of patients with PDN have the comorbidity symptoms of depression and anxiety. Regarding sleep problems, the cut-off point for sleep problems is 5. Therefore, according to data, the prevalence of sleep problems is 85.5%. That is, 85% of patients with PDN have significant problems related to sleep needing to follow.The present study has predicted the quality of life in patients with PDN based on pain severity, pain catastrophizing, pain acceptance, Depression, Anxiety, and sleep disturbance. Also, in this research, we estimated the prevalence of anxiety, depression, and sleep disorders/symptoms in Iranian patients with PDN. Correlation analyses demonstrated that QoL has a significant correlation with all predictive variables. The results collected from the regression analyses also showed that these variables could predict nearly half of the QoL PDN patients' variance. Depression has the most contribution to this equation. Pain catastrophizing achieved the second position, and the latest position belongs to anxiety.This is the first study for assessing the most prevalent psychological variables as predictors of QoL in PDN. However, the results are in line with previous researches. For example, a study examined correlations between anxiety, disability, and QoL in patients with PDN. Results showed that anxiety can reduce QoL both directly and indirectly (with increasing pain-related disability) in PDN . In anotOur research showed that pain catastrophizing has more portion than pain severity in QoL. Previous results are in line with this result too. For example, Lame et al. (2005) found that QoL is more correlated with beliefs about pain  than pain severity in chronic pain . These rBased on the present study, depression is the strongest variable in predicting QoL. Depression largely leads to physical disability. This disability reduces social participation, medical/psychological rehabilitation, and enjoyable activities. These factors, in turn, increase depression. Thus, the patient engages in a vicious cycle of depression and disability, which leads to severe depression and an extensive reduction in QoL. It has also been shown that the symptoms of depression lead to increased anxiety (anxiety symptoms) and sleep disturbance .Thus, deThe current study has several limitations. Our research is cross-sectional, and the results cannot be generalized to long-term patients’ life. Also, based on financial limitation we could not assess MRI evaluation. Future researches can assess the effectiveness of biopsychosocial treatment based on our equation. Also, researchers can assess the prevalence of other psychiatric problems in PDN and classify them by age. Another research topic can compare this equation before and after successful treatment and analyze the network shape of symptoms to determine core symptoms. Finally, future researches can assess network analysis about different psychiatric problem in patients with PDN.The current paper found that depression, pain catastrophizing, pain acceptance, pain severity, sleep disturbance, and anxiety determine 42% of QoL in patients with PDN. The order to determine a role in QoL from the strongest to the weakest is depression, pain catastrophizing, pain acceptance, pain severity, sleep disturbance, and anxiety. Also, in patients with PDN, the prevalence of sleep disturbances, depression, and anxiety are 85.5%, 68.2%, and 62.1%, respectively. Also, comorbid depression and anxiety were found to be 47%. So, it is essential to focus on these psychiatric symptoms in PDN to increase QoL and treatment outcomes.


SV) and inter-regional dynamic functional connectivity (dFC) in the interictal phase of migraine and its relationship with the attack severity.The moment-to-moment variability of resting-state brain activity has been suggested to play an active role in chronic pain. Here, we investigated the regional blood-oxygen-level-dependent signal variability (BOLDSV) and performed a whole-brain voxel-wise group comparison. The brain regions showing significant group differences in BOLDSV were used to define the regions of interest (ROIs). The SD and mean of the dynamic conditional correlation between those ROIs were calculated to measure the variability and strength of the dFC. Furthermore, patients’ experimental pain thresholds and headache pain area/intensity levels during the migraine ictal-phase were assessed for clinical correlations.We acquired resting-state functional magnetic resonance imaging from 20 migraine patients and 26 healthy controls (HC). We calculated the standard deviation (SD) of the BOLD time-series at each voxel as a measure of the BOLD signal variability  nuclei of the thalamus, primary somatosensory cortex (S1), and posterior insula. Conversely, migraine patients exhibited lower BOLDSV in the top-down modulatory pathways, including the dorsolateral prefrontal (dlPFC) and inferior parietal (IPC) cortices compared to HCs. Importantly, abnormal interictal BOLDSV in the ascending trigeminal spinal-thalamo-cortical and frontoparietal pathways were associated with the patient’s headache severity and thermal pain sensitivity during the migraine attack. Migraineurs also had significantly lower variability and greater strength of dFC within the thalamo-cortical pathway (VPM-S1) than HCs. In contrast, migraine patients showed greater variability and lower strength of dFC within the frontoparietal pathway (dlPFC-IPC).We found that migraineurs, compared to HCs, displayed greater BOLDMigraine is associated with alterations in temporal signal variability in the ascending trigeminal somatosensory and top-down modulatory pathways, which may explain migraine-related pain and allodynia. Contrasting patterns of time-varying connectivity within the thalamo-cortical and frontoparietal pathways could be linked to abnormal network integrity and instability for pain transmission and modulation. Migraine is a debilitating neurological disorder characterized by recurrent headaches episodes, often accompanied by amplified perception of multiple sensory inputs such as cutaneous allodynia, photophobia, and phonophobia –3. The sSV) had low pain sensitivity and better coping ability [SV in the ascending pain pathway and default mode network, and these abnormalities were related to pain symptoms [Moment-to-moment brain signal variability in fMRI resting-state, once regarded as just a noise and thus ignored in the neuroimaging field, has recently been proposed as an indicator of the brain function and its response to an environmental challenge –14. Addi ability . In contsymptoms , 17. Fewsymptoms , 10 and SV in migraine patients.Migraine in the interictal period also exhibited altered static functional connectivity in brain regions associated with nociceptive/antinociceptive processing , 18–21 aSV and dFC could be a useful measure to reveal altered cortical excitability and dysfunctional network dynamics that impact migraine attack and pain. To this end, we examined differences of resting-state BOLDSV, defined as the standard deviation of the BOLD signal, in interictal migraine patients compared to the HC group. Compared to the ALFF, calculated as the square root of the power within a specific frequency range, the standard deviation is a direct index of BOLD signal fluctuation in the time domain [SV in the ascending trigeminal somatosensory and the descending pain modulatory pathways compared to the HC group, and that abnormal BOLDSV would be associated with clinical and experimental pain during the migraine attack. Clinical and experimental pain, including migraine attack area/intensity (and their summation) and thermal pain threshold on the ophthalmic trigeminal region, were assessed during the patients’ ictal phase. In addition, we utilized dynamic conditional correlation (DCC) [In our study, we assumed that the resting-state BOLDe domain . We hypoon (DCC) , a relia(Table Twenty migraine (episodic or chronic) patients were recruited by local advertisement. Eligibility criteria for migraine patients were: 1) diagnosis as per the International Headache Society Classification (ICHD-3-beta) , (2) bet diagnosiMigraine-specific variables including disease duration, presence of aura, frequency of migraine attacks per month, and the six-item Headache Impact Test (HIT-6) , which mAll MRI data were collected from a 3 T GE scanner  at the University of Michigan. fMRI data were acquired using a reverse spiral sequence : repetitResting-state fMRI scan for migraine patients was performed during the interictal phase. During the resting-state fMRI scan, participants were instructed to keep their eyes centered on a visual fixation cross of the screen and try not to think of anything in particular, and relax. They were also asked to keep their head as still as possible during the scan. Head motion was minimized using foam pads placed around the head. The pulse oximeter was placed on the subject’s finger, and the pressure belt was placed around the abdomen of each subject so that the cardiac and respiratory signals were acquired simultaneously.http://www.nitrc.org/projects/fcon_1000) [http://www.fmrib.ox.ac.uk/fsl) and Analysis of Functional NeuroImages (http://afni.nimh.nih.gov/afni). After discarding the first five volumes, slice time correction, motion correction, grand-mean scaling of the voxel value, removing of eight nuisance signals  by regression, removing linear and quadratic trends, spatial smoothing using a Gaussian kernel of 6 mm full-width half-maximum, and temporal band-pass filtering  [3) standard space using FMRIB’s Linear Image Registration Tool.Resting-state fMRI data were reconstructed using field map correction and then corrected for cardiac- and respiratory-related noise . The folon_1000)  were con.198 Hz)  were perSV across low frequencies (0.01–0.198 Hz) and assessed group differences. It has been suggested that brain oscillation at an independent frequency band has specific properties and physiological functions [SV map was standardized into a subject-level Z-score map by subtracting the mean of BOLDSV across the whole-brain (gray matter) and then divided by the standard deviation of the BOLDSV across the whole-brain (gray matter) [SV is higher than the whole-brain, while a negative value indicated that BOLDSV is lower than the whole-brain. Voxel-wise group comparison was performed using an unpaired two-sample t-test. To ensure that head motion artifacts did not influence our results, we calculated the frame-wise displacement (FD) [t = − 1.391, p = 0.171); mean FD, as well as age and sex, were included as covariates in the statistical analysis to limit the potential effect of head micromovements on the BOLDSV measures [p < 0.05 (uncorrected height threshold of p < 0.001 [p < 0.05). Initial cluster-extent based correction  applied in the whole-brain comparisons did not capture a significant difference in the spinal trigeminal nucleus (SpV) due to its anatomically small size. To test our hypothesis of difference in BOLDSV in the SpV, we created an SpV mask with a 5-mm sphere region-of-interest (ROI) in the left  and right  SpV subnucleus caudalis and interpolaris [p < 0.05, FWE-corrected for multiple comparisons), which detects clusters of contiguous voxels without having to define an initial cluster-forming height threshold. The BOLDSV map of each subject was used as input data; and age, sex, and mean FD were included as covariates.First, we calculated the BOLDunctions . Thus, wunctions  to deter matter) . A positent (FD)  for eachmeasures . All resrpolaris  were pern = 13) or CM (n = 7) group. This comparison will address whether the observed BOLDSV alterations are valid for both migraine groups or only for a specific subgroup.After identifying the brain regions showing significant differences between migraine and HC, we further performed subgroup analysis . The 20 migraine patients were divided into EM , left thalamus  , left thalamus  , left dorsal posterior insula (dpINS) , and left primary somatosensory cortex (S1) . In the current results, the left thalamic cluster includes both PuM and VPM; thus, we generated 2 peak seeds including the PuM and VPM based the Morel’s 3D thalamus segmentation [x, y, z: 44, 22, 36), and inferior parietal cortex (IPC) . The ROIs were linearly transformed to each subject’s functional space, and the mean time series (0.01–0.198 Hz) across all voxels in the ROIs were extracted. Cross-correlation analysis was performed to test whether the BOLD signal fluctuation was temporally synchronized within the pathways showing higher or lower BOLDSV.Among the significant regions identified in the between-group comparison of the BOLDentation . Regardihttps://github.com/canlab/Lindquist_Dynamic_Correlation) [t-test. Statistical significance was set at p < 0.05.To measure the dynamic changes in functional connectivity between the same ROIs, we applied the DCC (elation) , which ielation) . Compareelation) . Also, Delation) . Howeverelation) , 45. TheSV and migraine headache severity, including P.A.I.N.S., pain VAS, and thermal pain threshold during the ictal phase, was assessed using Spearman correlation. The cross-correlation results revealed that BOLD signal fluctuation of the dlPFC and IPC were highly correlated, which indicate significant functional connectivity. Also, the location of the 2 clusters was overlapped with the right frontoparietal control network [SV (Z) of the right dlPFC and IPC was averaged. The Benjamini-Hochberg false discovery rate correction (q = 0.05) was applied for correcting multiple comparisons [The relationship between BOLD network . We assuparisons .t-test and chi-square test showed no significant difference between groups (migraine patients vs. HC) based on age (p = 0.428) and sex (p = 0.818). There was no significant difference between CM vs. EM patients for disease duration (p = 0.945), HIT-6 (p = 0.086), ictal thermal pain threshold (p = 0.202), ictal P.A.I.N.S. (p = 0.720), and ictal pain intensity (p = 0.246).Demographic and clinical characteristics of the study participants are shown in Table SV in the left thalamus encompassing the PuM and VPM, right thalamus (VPM), left dpINS, superior/middle temporal gyrus, right hippocampus, and left cerebellar vermis compared with HC subjects within the entire frequency range from 0.01 to 0.198 Hz   . Conversely, patients with migraine exhibited lower BOLDSV in the right dlPFC and IPC compared with HC subjects  Fig. , Table 2SV, frequency range was divided into slow-5 (0.01–0.027 Hz), slow-4 (0.027–0.073 Hz), and slow-3 (0.073–0.198 Hz). Within the slow-5 frequency band , migraine patients had greater BOLDSV in the left thalamus corresponding to the PuM but showed lower BOLDSV in the right IPC compared with HCs. In subgroup analyses, the CM group showed marginally lower BOLDSV in the right IPC (p = 0.07) compared with HCs. Within the slow-4 frequency band , we observed greater BOLDSV in the left PuM, dpINS, S1, and right thalamus encompassing VPM, and ventral posterolateral nucleus in the migraine patients compared with HCs. In contrast, BOLDSV in the right dlPFC, IPC, and left angular gyrus was significantly lower in migraine patients. In subgroup analyses, initial results remained similar except in some regions. BOLDSV in the right IPC (p = 0.16) and left angular gyrus (p = 0.10) was not significant between CM vs. HC. Within the slow-3 frequency band , we found greater BOLDSV in the right dpINS, hippocampus, left superior/middle temporal gyrus, cerebellar vermis, left thalamus encompassing medial dorsal nucleus, thalamic reticular nucleus, and ventral lateral nucleus; and the right thalamus encompassing the ventral posterolateral, lateral posterior nucleus, VPM, and PuM. Additional voxel-wise permutation tests with TFCE in the SpV mask confirmed that migraine patients displayed significantly greater BOLDSV in the bilateral SpV compared with HC subjects . Similar to other frequency bands, BOLDSV in the right dlPFC, angular gyrus, and bilateral IPC was significantly lower in migraine patients compared with HCs. In subgroup analysis comparing EM vs. HC and CM vs. HC, most of the regions were significant. However, greater BOLDSV in the bilateral SpV, left superior/middle temporal gyrus, and right hippocampus was only significant in EM compared to HC. The CM group showed lower BOLDSV in the bilateral SpV and right hippocampus compared to EM. Also, the CM group showed marginally lower BOLDSV in the right dlPFC (p = 0.08) compared with EM.To further verify frequency-specific perturbation in BOLD 0.01–0.07 Hz, slo 0.01–0.07 Hz, slo 0.01–0.07 Hz, slon = 46) cross-correlation (0.01–0.198 Hz) graph showed a significant correlation between pairs of regions. The results indicated that the BOLD signal fluctuation was temporally synchronized within the trigeminal spinal-thalamo-cortical pathway  and variability (p < 0.05) of dFC between VPM and S1  in CM patients compared with HC subjects, while the variability of dFC (VPM-S1) was lower (p < 0.01) in CM patients compared with HC subjects. There were no significant group differences in the dFC between the SpV and VPM, and between the VPM and insula . In the frontoparietal pathway, the strength of dFC between right dlPFC and IPC was decreased in migraine patients compared with HC (p < 0.01)  and CM (p < 0.05) groups. In addition, we found higher variability of dFC in EM patients compared with the HC group (p < 0.05).We then applied DCC analysis to characterize temporal dynamics of functional connectivity. The left and right panel of Fig.  S1 Fig. b. The st01) Fig. c. This dSV in the ascending trigeminal somatosensory pathway and migraine headache severity in the patient group. Patients with higher BOLDSV in the right SpV , left PuM , dpINS , and S1  had greater P.A.I.N.S. in the head and facial area . Also, correlation between headache pain intensity (VAS) and BOLDSV in the right SpV , left PuM , dpINS , and S1  were not significant after false discovery rate correction. In the frontoparietal pathway, patients with lower BOLDSV in the dlPFC and IPC had lower thermal pain threshold on the ophthalmic trigeminal region during migraine attacks   than HCs. In contrast, migraine patients showed higher variability and lower strength of dFC in the frontoparietal pathway (dlPFC-IPC). Finally, we demonstrated that dysfunctional interictal BOLDSV in the ascending trigeminal somatosensory pathway and frontoparietal pathways were correlated with the patient’s headache severity and thermal pain sensitivity during migraine attacks.Our results revealed that migraineurs displayed significantly greater BOLDIt is noteworthy that migraineurs exhibited greater temporal variability of BOLD signal in the trigeminal somatosensory pathway, which is involved in the core pathophysiology of migraine . For exaSV in this pathway and individuals’ P.A.I.N.S. during migraine attacks supports this interpretation. Taken together, increased resting-state brain signal instability in the trigeminal somatosensory pathway may contribute to an abnormal pain and sensory gain during and even outside of migraine attacks [It has been suggested that greater signal variability was known to reflect a greater range of neuronal responses, which is achieved by balanced synaptic excitation and inhibition, for better adaptive function in a given environment , 57. How attacks .SV in the trigeminal somatosensory pathway and altered thalamo-cortical dFC are in agreement with thalamo-cortical dysrhythmia in interictal migraine [Our findings of abnormally increased BOLDmigraine , 58–61 amigraine , 62, 63.migraine  evoked hmigraine . A recenmigraine . These rmigraine . Togethemigraine .SV within the frequency range from slow-5 to slow-4 was located in the left PuM. The medial pulvinar is the higher-order relay nucleus of the thalamus. It has a reciprocal connection with the higher-order cortex and paralimbic areas, including prefrontal, posterior parietal, insula, and parahippocampal cortices [In previous resting-state fMRI studies in migraine, increased amplitude of low-frequency oscillation was found in the medial dorsal nucleus of the thalamus in slow-4 (0.027–0.073 Hz) band . This recortices . Thus, aImportantly, migraine patients displayed less variability of dFC accompanied with the increased strength of dFC between VPM and S1 compared with the HC group. These abnormalities were prominent in the CM group. The VPM and S1 are thought to be involved in trigeminal nociceptive information processing . It was SV in the higher-order prefrontal and parietal association cortex in migraine patients compared to HCs. The dlPFC and posterior parietal cortex are critically involved in the pathophysiology of chronic pain, including migraine [SV in the dlPFC and IPC regions could result in inadequate top-down pain modulatory function. We confirmed this by demonstrating a significant correlation between decreased BOLDSV in the dlPFC-IPC and lower thermal pain threshold on the ophthalmic trigeminal region measured during migraine attacks. This argument accords with the view that interictal dysfunction of the descending pain modulatory system could contribute to central sensitization during migraine attacks [We found lower BOLDmigraine –72. In omigraine . Both thmigraine –76. It hmigraine , 77. Thu attacks , 78.Moreover, we found increased variability along with reduced strength of dFC between right dlPFC and IPC in EM patients. The frontoparietal network has been reported to play an important role in cognitive control and top-down modulation of pain . Thus, oSV in the S1 (ascending pain pathway) and posterior cingulate cortex (default-mode network) could predict patients’ average (trait) pain [SV during the interictal period can be used to predict trait-like migraine characteristics such as the severity of the migraine attack.It was indicated that temporal variability of resting-state BOLD signal and dynamic network connectivity would be related to trait-like (longer-lasting) pain characteristics. Using a machine learning approach, Rogachov and colleagues demonstrated that baseline BOLDit) pain . Furtherit) pain . In our SV analysis included both EM and CM for the patient group, and thus the results may not be specific for either EM or CM. However, the subgroup analysis confirmed that both EM and CM groups have comparable abnormalities of BOLDSV in most of the significant regions. Future studies are warranted using a larger sample size of migraine patients to confirm the validity and reliability of the current results and to provide more specific information regarding migraine subtype . Lastly, although we intent to match the sex ratio between diagnostic groups (migraine vs. HC) and adjust potential sex effect on the BOLDSV in statistical analyses, the entirety of the CM group being female may limit the applicability of the subgroup analysis and thus the results may be affected by that factor. An extension study with larger sample size and a balanced sex ratio between subgroups is warranted.Some limitations need to be considered when interpreting the data. Resting-state BOLDSV in the ascending trigeminal somatosensory pathway and frontoparietal pathways were associated with the patient’s headache severity and thermal pain sensitivity during migraine attacks. Contrasting dFC patterns in the thalamo-cortical (VPM-S1) and frontoparietal (dlPFC-IPC) pathways could be linked to abnormal network integrity and instability for pain transmission and modulation.Our study provides evidence of altered brain dynamics by demonstrating bi-directional changes in signal variability and time-varying connectivity within the ascending trigeminal somatosensory vs. top-down modulatory pathways in migraineurs. We demonstrated that dysfunctional interictal BOLD


Neuropathic pain remains poorly treated, with most new drugs falling through the translational gap. The traditional model of bench-to-bedside research has relied on identifying new mechanisms/targets in animal models and then developing clinical applications. Several have advocated bridging the translational gap by beginning with clinical observations and back-translating to animal models for further investigation of mechanisms. There is good evidence that phenotyping of patients through quantitative sensory testing can lead to improved treatment selection and hence improved patient outcomes. This practice has been widely adopted in clinical investigations, but its application in preclinical research is not mainstream. In this review, we retrospectively examine our historical rodent data sets with the aim of reconsidering drug effects on sensory neuronal endpoints, their alignment with clinical observations, and how these might guide future clinical studies. A loss-of-function mutation renders the carrier analgesic, thus validating the target.1 Blockers of this channel are being developed but are not generally available for human use. In the case of inherited erythromelalgia, a gain-of-function alteration in the channel, the particular mutation in the amino acid sequence confers differential sensitivity of individual patients to the nonspecific sodium channel blockers carbamazepine and mexiletine.3 This suggests that even with a genetic basis for the pain disorder, drug choice can be complicated. In the case of neuropathic pain, a number of drugs with very different mechanisms of action are approved but the numbers needed to treat is high, circa six, indicating that only a minority of patients will gain relief with a particular drug.4 This is perhaps not surprising, because although peripheral neuropathic pain originates at the site of the damaged nerves, there are considerable pharmacological changes at this level as well as many and varied changes in the spinal cord, brain, and descending controls. Because each drug has a defined action, one could presume that in order to treat the pain adequately, the drug would have to target the predominant mechanism active in that patient.In many areas of medicine the aim is to move toward personalized or precision treatments so that the therapy matches the cause of the condition. Emphasis has been on defining the genetic cause, but it is rare that a single gene mutation forms the basis for a disorder, and even if this is the case a therapy that manipulates the gene produce is often lacking. In the case of pain, the best characterized genetic bases are mutations in sodium channels with loss and gains of function, depending on the particular changes in Na5 Similar separable subgroups of patients have been identified among patients with fibromyalgia and postsurgical pain, suggesting that the heterogeneity crosses pain syndromes. Failing to take this into account means that the patients in the trials were very likely to be heterogeneous in terms of mechanisms and thus drugs that were effective in some patients would not be observed and the trial and drug would fail. Consequently, the idea of a mechanism-based rationale for bench-to-bedside translation when screening novel drugs is a crucial point because it will guide the trial design.In the rest of this review, we will discuss a number of other drugs used for neuropathic pain and their profiles in preclinical models. There is a key issue here regarding translation. If a drug has effects on particular responses or modalities, then many drugs may have failed in clinical trials where patients were simply included based on a particular etiology, whether postherpetic, diabetic, HIV, or chemotherapy-induced neuropathy. It has been clearly shown that independent of the etiology, patients with neuropathic pain fall into three subgroups, based on their sensory profiles determined through quantitative sensory testing .7 and these tests provide additional insight into the affective/aversive dimension of pain. These measures of cognitive function may be more translatable than reflexive endpoints. Neurophysiology can overcome some of these limitations by providing a quantitative and objective measure of sensory neuronal transmission. Microneurography, for example, can be performed in both rodents and humans,8 and numerous studies have established the relationship of second- and third-order neuronal firing with perceptual outcomes.9–12 We retrospectively examine the effects of drugs on this latter neuronal endpoint in rats from our historical data sets .Despite accumulating vast global annual sales, the α29 Although only a single example, it illustrates how careful dissection of mechanisms can distinguish different pains and perhaps aid treatment selection. It is conceivable that in clinical trials, patients with mixed pains may report insufficient pain relief due to targeting of a single neurobiological mechanism. When tested against QST endpoints in a small group of patients with peripheral neuropathy, chronic gabapentin treatment reduced brush allodynia and raised cold pain thresholds where these sensory disturbances were present but had no effect on heat detection or pain thresholds in all patients tested or any effect on punctate mechanical stimuli in patients with mechanical hyperalgesia.30 Although low in numbers, this study displays some concordance with the effects of acute pregabalin on sensory neuronal processing in rats with peripheral nerve injury because brush-evoked neuronal responses were inhibited and heat-evoked responses were only weakly affected, but contrasting effects were seen with respect to cold and mechanical stimuli.31 In the rat models at least, the gabapentinoids are particularly effective at inhibiting high-intensity mechanically evoked neuronal responses. On a larger scale, post hoc analysis of clinical trial data revealed that pregabalin had no benefit in patients with HIV neuropathy but provided pain relief in a patient subgroup characterized by severe pinprick hyperalgesia.32 A more recent study of patients with chemotherapy-induced neuropathy found that mechanical pain thresholds were not predictive of response to pregabalin, though the number of patients exhibiting mechanical hypersensitivity was low,33 and the former study noted that only those patients with the most severe pinprick hyperalgesia benefited, whereas those with mild/moderate hyperalgesia did not. Baron and colleagues proposed that these patients are represented by the mechanical cluster  block37—and patients with neuropathy with enhanced temporal summation are more likely to benefit from ketamine treatment.38 In pain-free volunteers, the ability of gabapentin and pregabalin to inhibit temporal summation of pain is dependent on the sensitization state.40 Data from animal models are rather mixed; neither gabapentin nor pregabalin inhibits windup in uninjured rats, but whether windup is inhibited in neuropathy seems to depend on the precise nature of the nerve injury.41–43 Supraspinal analgesic mechanisms of the gabapentinoid drugs include activating descending inhibitory pathways,44 though at present there appears to be no report of whether they improve CPM in patients with neuropathy. In a nonneuropathic condition such as pancreatitis, pregabalin had no effect on low CPM responses.45 In rats at least, pregabalin does not restore deficient DNICs in a model of knee degeneration where disrupted descending modulation forms part of the etiology of persistent joint pain.46Windup and temporal summation of pain and conditioned pain modulation are two measures that could merit further investigation. Windup is commonly interpreted as a readout for sensitization state. Electrically evoked windup produces hyperexcitability of spinal neurons that induces transient features that are shared with central sensitization, such as enlarged receptive field sizes and windup at lower frequencies.v2.2.47 The poor blood–brain barrier penetration necessitates delivery via the intrathecal route and, due to this impracticality, it is most commonly used in cases refractory to treatment by other drugs. Ziconotide can provide relief for many of these patients, validating targeting of calcium channels for treatment of neuropathic pain.48 Like the conotoxins, the spider toxin Tx3-3 has broad inhibitory effects on spinal neuronal responses consistent with its lack of selectivity over channel subtypes and activation state.49 The development of small molecule activation state-dependent blockers was intended to circumvent the neurological side effects that can be associated with peptide blockers, the hypothesis being that targeting of calcium channels in hyperexcitable primary afferents would block aberrant nociceptive signaling while permitting normal sensory transmission. Several of the developed compounds  displayed good tolerability within phase I trials but failed to demonstrate efficacy in phase II . In line with the predicted mechanism of action, the activation state-dependent but non-subtype-selective Cav2 blocker TROX-1 has no effect on normal sensory transmission but exhibits modality-selective effects in neuropathic rats, only inhibiting responses evoked by punctate mechanical stimuli.50 All of the failed trials selected patients on the basis of disease etiology and did not distinguish between those with sensory gain and sensory loss. Drawing parallels with the oxcarbazepine trial, these drugs may be particularly effective where pain is driven by peripheral hyperexcitability and evoked pain is the primary sensory disturbance.Gabapentin was in use as an anticonvulsant but found new purpose as an analgesic following a clinical observation. One of the rare success stories for bench-to-bedside translation was the discovery that intrathecal ω-conotoxin was antinociceptive, which led to the development of ziconotide, a synthetic peptide blocker of the voltage-gated calcium channel Ca51 Subsequently, it has been shown that these neurons are part of the spinothalamic tract, code the intensity and spatial summation of a noxious thermal stimulus in an overlapping way with the human pain ratings to the same stimulus,12 and exhibit both peripheral and central sensitization after ultraviolet B radiation and heat, corresponding with the human psychophysical correlates of the same model.11 This correspondence between neuronal coding  and human sensory reports is likely the basis for why CPM, the human counterpart of DNICs, can be readily established in volunteers and patients. In many patients with persistent pain there is a reduction in CPM, and a low CPM at the time of surgery is a risk factor for persistent pain.53 Have tested CPM in patients and studied the interaction between pain control and this descending inhibitory system. Duloxetine  and tapentadol  were tested in patients with diabetic neuropathy. Duloxetine efficacy was predicted by CPM in that low or lost CPM correlated with drug effectiveness, whereas tapentadol restored CPM as its analgesic effect appeared.55 Both studies are explained by the subsequent preclinical finding that DNICs were fully mediated by noradrenaline acting at the α2-adrenoceptor, that it was lost in models of nerve injury and could be restored by both tapentadol and reboxetine, the noradrenaline reuptake inhibitor.56 Very similar findings were seen in a model of osteoarthritis, in agreement with human data where CPM is lost in many pain states.57Over 40 years ago, DNICs were described whereby a distant noxious stimulus would inhibit the responses of spinal wide dynamic range neurons through descending controls.3R) and ketanserin (5-HT2AR).58 When given spinally, the former drug restores DNICs and has an enhanced action on sensory coding of spinal and thalamic neurons in models of nerve injury.58 Two human studies have used the drug in patients with neuropathy, and one was positive when ongoing pain was the outcome measure, whereas the other, looking at dynamic allodynia and ongoing pain, was negative.60 However, these discrepant results are explicable on the basis that the drug has differential effects on neuronal coding with modulation of punctate mechanical and heat stimuli but no effect on brush or ongoing activity. This emphasizes the point that clinical studies may “fail” if the wrong endpoints are picked.DNICs are noradrenergic inhibitors but are balanced by descending facilitations mediated by 5-Hydroxytryptamine (HT) largely through the 2A and 3 receptors. A large number of preclinical studies have shown that a loss of descending inhibition, normally protective, is accompanied by a gain of facilitation as pain becomes persistent, and recent human imaging studies in very different pain states, namely, fibromyalgia and severe osteoarthritis, report similar findings. These serotonergic enhancements of pain can be blocked by antagonists such as ondansetron (5-HTIt is becoming increasingly clear that pharmacological agents for the treatment of neuropathic pain have differential effects on different modalities/ongoing activity and that this can be readily examined in preclinical models measuring the activity of spinal and brain neurons. Therefore, designing a trial based on etiology seems highly likely to fail to identify those patients who will respond to treatment, and indeed many have failed in recent years. Simple reflexive withdrawal responses in preclinical development of drugs are not able to dissect out the nuances of drug actions and thus will not be helpful in providing a basis for mechanism-based treatments. Behavioral assays requiring cognitive processing offer greater insight but are not suited to measuring windup/temporal summation or DNICs where neurophysiological measures are advantageous. From this account, we would recommend a reconsideration of some of the pharmacological agents that have failed in trials based simply on etiology. Most of the preclinical and clinical data are based on neuropathic pain, but the same principles may apply to other important conditions such as osteoarthritis and fibromyalgia.


Percutaneous stabilization for spinal trauma confers less blood loss, reduces postoperative pain, and is less invasive than open stabilization and fusion. The current standard of care includes instrumentation removal.  1. Reporting patient outcomes following minimally invasive posterior percutaneous pedicle screw-rod stabilization (PercStab). 2. Evaluating the results of instrumentation retention.  A prospective observational study of 32 consecutive patients receiving PercStab without direct decompression or fusion. Baseline data demographics were collected. Operative outcomes of interest were operative room (OR) time, blood loss, and length of hospital stay. Follow-up variables of interest included patient satisfaction, Numeric Rating Scales for Back and Leg (NRS-B/L) pain, Oswestry Disability Index (ODI), and return to work. Clinical outcome data (ODI and NRS-B/L) were collected at 3, 12, 24 months and continued at a 24-month interval up to a maximum of 8 years postoperatively. n = 26) retained their instrumentation and reported minimal disability, mild pain, and satisfaction with their surgery and returned to work (mean = 6 months). Six patients required instrumentation removal due to prominence of the instrumentation or screw loosening, causing discomfort/pain. Instrumentation removal patients reported moderate back and leg pain until removal occurred; after removal, they reported minimal disability and mild pain. Neither instrumentation removal nor retention resulted in complications or further surgical intervention.  81.25% of patients ( PercStab without instrumentation removal provided high patient satisfaction, mild pain, and minimal disability and relieved the patient from the burden of finances and resources allocation of a second surgery. Spine fractures compromise approximately 6% of all fractures worldwide , 2. SurgAs this is a nonfusion technique, the current standard of care following minimally invasive posterior percutaneous pedicle screw-rod stabilization (PercStab) includes instrumentation removal . There iThe objectives of this study were (1) reporting patient outcomes following minimally invasive posterior percutaneous pedicle screw-rod stabilization to treat spine trauma and (2) evaluating the results of instrumentation retention.A prospective observational study monitored 32 consecutive spine trauma patients meeting inclusion criteria: age of 18 years or older with unstable spinal trauma for which PercStab was the course of treatment. Baseline data collection included patient age, sex, body mass index (BMI), comorbidities, mechanism of injury (MOI), Injury Severity Score (ISS), AOSpine Classification system, numeric pain rating scale, and admission diagnosis. Operative variables of interest included operative room (OR) time, instrumentation type, blood loss, length of hospital stay, levels operated on and surgical morbidity/mortality. Outcome variables of interest are the Numeric Rating Scales for Back and Leg (NRS-B/L) pain, Oswestry Disability Index (ODI), patient satisfaction, and time to return to work. Clinical outcome data (ODI and NRS-B/L) were collected at 3, 12, 24 months and continued at a 24-month interval up to a maximum of 8 years postoperatively. Patient satisfaction was collected at the patient's final follow-up. When applicable, timing of instrumentation removal and reasoning was reported.The AOSpine Classification system has been shown to have reasonable reliability and accuracy for clinical validation of a unified system to effectively communicate case-specific details of patient injuries , 18. TheInstrumentation removal was not applied as a standard. Instrumentation removal was provided based on clinical complaint, physical exam findings, and imaging findings at the discretion of the surgeon and in shared decision-making with the patient. Without specific justification, instrumentation was not removed.All patients received PercStab under general anesthesia. The patient was positioned prone on the OSI spine table with chest, hip, and leg bolsters placed to optimize alignment at the fracture site. Standard antiseptic skin preparation and draping was completed, and preoperative antibiotics were provided. Two C-arm fluoroscopy units provided simultaneous anteroposterior (AP) and lateral imaging capabilities. AP fluoroscopy guided placement of 1.5 cm stab incisions overlying each pedicle to be instrumented. The Pedicle Access Kit cannulated trochar (Medtronic Sofamor Danek) was tamped through the pedicle assuring that the tip of the trochar remained lateral to the medial pedicle wall at all times until the tip of the trochar passed into the vertebral body. Trochar position was confirmed on AP and lateral C-arm imaging. Guidewire was passed through the trochar followed by trochar removal. Guidewires were placed at each pedicle to be instrumented. The pedicles were then tapped, and cannulated screws were placed by hand.The pedicle screw-rod construct was placed utilizing the Longitude or Sextant II systems . The Sextant II system was utilized if the construct spanned one or two motion levels. The Longitude system was utilized if the construct was greater than two motion levels. Screws of 6.5 mm diameter were most commonly utilized. Screws were positioned to optimize construct stability and fracture alignment. If the spine and traumatic pathology permitted, screws were placed at the level of pathology as well. Bilateral titanium rods, 5.5 mm in diameter were measured, contoured, and passed in a subfascial plane through the pedicle screw extenders. Construct and fracture alignment were optimized with compression and distraction maneuvers, and final tightening of the set screws was completed. Insertion tools were removed. Final AP and lateral C-arm imaging were used to confirm the appropriate instrumentation placement and spinal alignment. Incisions were closed in layers and dressing was applied.The sample includes thirty-two consecutive trauma patients .PercStab as a surgical option resulted in no surgical induced morbidity/mortality but injury related morbidity preoperatively was seen in 21.87% of the sample which included superventricular tachycardia, blood abnormalities, urinary retention, low hemoglobin, sepsis, compromised respiratory function, and exacerbation of injuries due to poor compliance. Operative room morbidity was seen in 6.2% of the sample which included coagulation abnormalities and respiratory decline during intubation. Postoperative morbidity was seen in 35.9% of the sample which included poor pain control, hypervolemia, oxygen saturation fluctuations, low oxygen, The majority of patients in this case series, 26 of 32 .Our case series supports the previous literature demonstrating favorable outcomes following MIS management of spinal trauma independent of removal or retention , 15, 25.Previous research investigating PercStab as a treatment for thoracic and lumbar spine fractures followed a criteria of instrumentation removal as the standard of care; however, Yang et al. 2011) reported a small subset of their samples (10.94%) declined the second operation as the patients reported high satisfaction with their results [ reportedRemoval is usually done to avoid an instrumentation failure, loosening at the bone-screw interface, or other instrument related complications . In the Patients who retained their instrumentation were also older on average, had a lower incidence of polytrauma at admission, shorter average hospital stay, and fewer levels operated on. Comorbidities did not appear to influence removal though the low rate of reported comorbidities in the current sample (15.62% of the sample) could be responsible for this finding. None of these patients required removal.Limitations of the presented study include the fact that it is a case series so no cause and effect conclusions can be drawn. The current case study had a variable final follow-up time with the majority having final follow-up at 4 years (range 4–8). It would be beneficial to extend the follow-up to ensure facet arthrosis and possible instrument failure do not occur at a later time. However, sustaining follow-up rates becomes more problematic as the time extends. The current study has a reasonably small sample and the proportion of patients needing removal could change with a larger population. Despite the limitations mentioned given the patient outcomes reported, we would suggest that compulsory instrumentation removal is not always required following minimally invasive percutaneous screw-rod stabilization for thoracolumbar pathology. Instrumentation removal can be safely guided by clinical complaints. Average follow-up of 4 years would suggest that no risk is posed to these patients by instrumentation retention. In fact, minimal pain and disability with good work capacity can be realized despite instrumentation retention. Thus, the elimination of a second surgery for instrumentation removal as a treatment standard could be considered.Minimally invasive percutaneous screw-rod stabilization for thoracolumbar pathology resulted in high levels of patient satisfaction, minimal disability, mild pain, and high return to work with low perioperative risk. These findings were sustained despite eliminating the second surgery for instrumentation removal usually performed following this nonfusion procedure. While instrumentation removal may be provided for specific indications, removal in all cases may be unnecessary.


Peripheral nerve stimulation may be an alternative option to treat severe facial pain. We assessed the application of peripheral nerve stimulation for pain management in patients with herpes zoster ophthalmicus.A retrospective analysis was conducted in patients suffering severe facial pain caused by ophthalmic herpetic lesions. We identified the change in pain severity before and after peripheral nerve stimulation for up to 12 months.n = 18) and 5.4 ± 1.4 (n = 11), respectively. The prevalence of postherpetic neuralgia was 7% (1 out of 15) in the subacute pain group. No obvious adverse effect was observed.Eighteen patients were enrolled. Their mean age was 70.8 ± 9.5 years. Fifteen patients presented with subacute pain for 1–3 months, and three patients suffered postherpetic neuralgia. Dramatic relief from pain was achieved in 83% of patients (15 out of 18) upon initial removal of the stimulator, with pain reduction of > 50%. The long-term analgesic effect was reported at the 6- and 12-month follow-ups, with reductions in the visual analog scale of 4.8 ± 1.2 (Peripheral nerve stimulation may be an efficacious and safe approach for pain control in patients with herpes zoster ophthalmicus. Herpes zoster ophthalmicus (HZO) is a viral disease associated with the first branch of the trigeminal nerve . It has been estimated that about 10–20% of herpetic infections affect V1 . HZO preRoutine medical therapy for HZO comprises antiviral drugs, topical corticosteroids, and analgesics . Early aRecently, peripheral nerve stimulation (PNS) has increasingly been used to treat intractable headache disorders such as migraine and cluster headache through the stimulation of the occipital nerve . AdditioThe branches of the trigeminal nerve as well as the Gasserian ganglion are considered the targets of PNS therapy for facial pain . SpecifiThe evaluation of patient medical records was approved by the ethics board of the Third Xiangya Hospital of Central South University .Patients’ medical records were reviewed to identify those who were diagnosed with HZO and who subsequently underwent PNS between 2018 and 2019. The diagnosis of HZO was made according to the characteristic vesicular rash and dermatomal pain associated with the distribution of V1. One brief questionnaire was given to the patients to evaluate general information, duration of preoperative pain, medication use, and postoperative pain relief.A detailed description of the PNS procedure has been described by The PNS electrodes were retained for ≤ 14 days to avoid potential infection. The duration of electrode implantation for each patient is shown in The primary outcome was the change in pain intensity after PNS. This was evaluated by a visual analog scale (VAS) ranging from 0 (“pain free”) to 10 (“worst pain imaginable”). The postoperative VAS score was compared with that at baseline before implantation, and a decrease in the VAS score indicated pain relief. Patients who had pain relief ≥ 50% on the VAS after PNS were classified as “responders.” To identify the long-term analgesic effect of PNS, a telephone interview was conducted 1, 3, 6, and 12 months after discharge from hospital. “PHN” was defined as chronic neuropathic pain with a VAS score > 3 and symptom duration > 3 months, as described previously .P < 0.05 was considered significant. Data were analyzed using Prism v8 .Descriptive analysis was used to capture the general characteristics of patients. Variables are presented as the mean ± standard deviation. Paired comparisons of pain scores before and after PNS were made using the Wilcoxon signed-rank test. Eighteen patients  who received PNS therapy were identified. The mean age of patients was 70.8 ± 9.5  years. All patients presented with severe pain associated with the ophthalmic nerve after an initial herpetic skin rash, characterized by a burning, throbbing, stabbing, shocking pain. Most (15 out of 18) cases had suffered subacute facial pain for 1–3 months. Three patients developed chronic postherpetic neuralgia over 3 months. Thus, we divided the cohort into two subgroups according to symptom duration . FifteenAll patients were followed up on at 1, 3, and 6 months after their hospital discharge. A final follow-up was accomplished for 11 out of 18 patients, at 12 months after PNS. The pain scores collected at each follow-up are given in n = 3) in the PHN group and 80% (12 out of 15) for the subacute-pain cohort. PNS provided instant and significant pain relief compared with the pain measured at the baseline  upon initial removal of the stimulator . The resbaseline . Two patn = 18) at the 6-month follow-up and 5.4 ± 1.4 points (n = 11) at 12-month follow-up, respectively  were observed in this study.Patients suffer severe and long-lasting facial pain with HZO. The high risk of PHN is associated with ophthalmic involvement . Conventional intervention remains insufficient to control HZO pain. Thus, improving the pain management of HZO patients and preventing PHN development are important tasks.Early antiviral therapy can attenuate acute herpetic pain and reduce the risk of PHN . HoweverMultimodal analgesia plays an important role in solving the undertreatment of pain. Neuromodulation therapy is a key component of a multimodal-analgesia strategy, and has been used to alleviate intractable neuropathic pain, such as “phantom limb pain” . MeanwhiRecent innovations in PNS have indicated its potential role in the treatment of intractable facial pain . HoweverTimely management of pain is crucial to prevent the chronicity of HZO. Our study focused, for the first time, on a population of patients with subacute HZO-related pain who received PNS. We demonstrated that 80% (12 out of 15) of patients with subacute HZO-related pain experienced > 50% pain relief when discharged. Only one out of 15 patients (7%) developed PHN in the subacute group 3 months after the initial skin rash. Our study had three main limitations. First, it was retrospective. Second, it had an uncontrolled design. Third, the details of analgesic use were not recorded systematically. Randomized controlled trials are needed to confirm our findings of the superiority of PNS compared with conventional treatments for HZO-related pain.PNS was demonstrated to achieve instant and effective pain control for HZO patients. The long-term effect of PNS was enduring, with a low prevalence of PHN. For HZO patients who suffer severe pain with conventional therapy, PNS may be a promising option.The original contributions generated for this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by the ethics board of the Third Xiangya Hospital, Central South University. Written informed consent was signed before PNS therapy. The procedures and data analysis in this study were conducted in accordance with the research guideline of Third Xiangya Hospital Institutional Review Board.HZ and DH designed the study. RuH, GG, YN, JZ, and DH carried out the procedures. XL, ZW, LY, and RoH conducted the follow-ups. XL and HZ conducted the data analyses. HZ wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Only a small percentage of pediatric chest pain is of cardiac origin and the most common detected cause is musculoskeletal. Among musculoskeletal causes, acute chest pain is better described, with the causes of chronic pain not being adequately investigated in the literature. The aim of studuy is to evaluate the musculoskeletal causes of non-cardiac chest pain and investigate the relationship of chest pain with child abuse and central sensitization.Patients aged 12 to 18 years presenting with chest pain for at least 3 months were evaluated by a pediatric cardiologist and those without an organic pathology were referred to the physical medicine and rehabilitation clinic. In addition to detailed history and physical examination, juvenile fibromyalgia was questioned according to the 2016 revised diagnostic criteria of the American College of Rheumatology. The visual analog scale (to measure intensity of chest pain), the Central Sensitization Inventory , the Hospital Anxiety Depression Scale (to determine depression and anxiety), the Childhood Trauma Questionnaire (to assess the presence of child abuse) were administered.n = 17) were diagnosed with juvenile fibromyalgia, and central sensitization was detected in 34.4% (n = 22). Pain intensity, anxiety, depression and abuse scores were higher in patients with juvenile fibromyalgia than those without juvenile fibromyalgia and in patients with central sensitization compared to those without central sensitization (p < 0.001 for both). Higher scores of pain were related with child abuse  and central sensitization of pain  in regression analyses.The study was completed with 64 patients. Twenty-six percent of patient (In this study, juvenile fibromyalgia was detected as a cause of non-cardiac chest pain. Juvenile fibromyalgia or central sensitization may also indicate childhood abuse. Chest pain is a common complaint of referrals to the cardiology clinic in the pediatric population. However, only 1% of patients presenting to pediatric cardiology with chest pain have a true cardiac pathology, with 99% being of non-cardiac origin. The most common detectable cause is musculoskeletal, although pulmonary, gastrointestinal, psychogenic and idiopathic factors can also be seen .The most common musculoskeletal causes of chest pain are costochondritis, muscular strain, rib fracture, and trauma, which all cause acute pain. It is reported in the literature that idiopathic chest pain has a longer symptom duration than costochondritis-induced chest pain . This suJuvenile chronic musculoskeletal pain is characterized with pain lasting at least 3 months with reported frequencies as much as 5–20%. Of these children, 25–40% meet the criteria of juvenile fibromyalgia (JFM), which is characterized by chronic diffuse pain and accompanying fatigue and sleep, sensory, autonomic and cognitive disorders . ReducedThis prospective study was approved by the ethics committee of the tertiary care hospital. Written consent was obtained from all children who participated in the study and their parents. Patients aged 12 to 18 years presenting to the pediatric cardiology clinic from January 2018 to October 2019 with the complaint of chest pain lasting longer than 3 months without cardiac, pulmonary and gastrointestinal causes were included in the study. All patients underwent a detailed cardiac evaluation, including history, physical examination, chest radiography, electrocardiography, echocardiography and exercise test by the same physician. For those with suspected cardiac origin, the biomarker tests of myocardial injury were also undertaken. The patients with any cardiac or gastrointestinal or pulmonary diseases were excluded from the present study. Those with previous thoracic surgery, trauma history, chronic systemic disease, organic central nervous system disease, mental retardation, and known psychiatric disease or receiving anxiety or antidepressant/psychotropic medications prior to or for the duration of study enrollment were also excluded. Figure After the evaluation of pediatric cardiologist, the detailed history was obtained and a physical examination was performed by the same physical medicine and rehabilitation physician to investigate musculoskeletal diseases. The characteristics of the pain profile such as morning stiffness, nighttime pain, fever, inflammation, and other red flags for pain, and factors associated with increasing and decreasing of pain were questioned. During the physical examination, the chest wall and joints were palpated. In patients detected to have a postural disorder, a radiographic examination of the spine  was also evaluated. All patients were evaluated the presence of generalized hypermobility or Ehler-Danlos Syndrome . For thothe 10-cm Visual Analog Scale (VAS) for pain was administered to all patients to determine the intensity of chest pain. VAS is a Likert-type scale, with a score ranging from 0 to 10 to evaluate pain intensity. A score of 0 indicates no pain while 10 refers to the most severe pain.After the diagnostic procedures, The Central Sensitization Inventory (CSI) was used to evaluate the presence of central sensitization. CSI, which can be applied in the presence of chronic pain, is especially utilized in central sensitization syndromes, including fibromyalgia. CSI consists of two parts: Part A is a Likert-type scale that contains 25 questions related to the frequency of health-related symptoms from never (a score of 0) to always (a score of 4). The total score ranges from 0 to 100, and a high score is associated with a high degree of central sensitization. A score of 40 or higher indicates the presence of central sensitization. Part B investigates whether the patients were previously diagnosed with any of the central sensitization syndromes [yndromes . The valyndromes .The Hospital Anxiety and Depression Scale (HADS) was used to determine the presence of anxiety and depression. HADS consists of a total of 14 items, of which seven question depression and seven anxiety. Each item is scored from 0 to 3. The items related to depression and those related to anxiety are summed separately. In each section, 0–7 is scored as normal, 8–10 as borderline abnormal, and 11 and above as abnormal values [l values .The Childhood Trauma Questionnaire (CTQ), developed by Berstein et al., was applied to evaluate childhood abuse. CTQ consists of 40 items based on a Likert scale, scored from 1 (never) to 5 (very often). The minimum and maximum scores are 40 and 200, respectively, with high scores indicating a higher frequency of abuse. CTQ has three subscales evaluating emotional abuse (19 items), physical abuse (16 items), and sexual abuse (five items) [al abuse  items, ae items) .All of these questionnaires were administered to the patients individually in a comfortable environment through face-to-face interviews by the same physician.p < 0.05.Statistical analysis was performed using the Statistical Package for the Social Sciences software . The normal distribution was evaluated using visual and statistical methods. Nominal variables were given as numbers and percentiles, and quantitative data as mean and standard deviation when the data was normally distributed and as median and interquartile ranges if the data distribution was not normal. For the comparison of the two groups, the independent samples t-test was conducted for quantitative data in the presence of normal distribution and the Mann-Whitney U test for the data without normal distribution. To evaluate the correlation between the variables, Pearson’s correlation and Spearman’s correlation analyses were undertaken for the normally and non-normally distributed data, respectively. A regression analysis was performed to predict the correlated data. Significance was evaluated at Totally, 125 adolescent patients were analyzed to inclusion criteria and 64 patients were included into the present study. The mean age of included 54 girls and 10 boys was 15.0 ± 1.8 years, and the mean age at onset of chest pain was 13.3 ± 2.2 years. The median duration of symptoms was 12 (interquartile range 4.25–24) months. No patients reported a family history of psychiatric illness or close family history of fibromyalgia/anxiety, depression, and any family history of non-cardiac chest pain. JFM was detected in 17 patients (26%) in according to the 2016 revised version of the 2010 American College of Rheumatology (ACR) fibromyalgia syndrome diagnostic criteria.Spine x-rays showed abnormal findings in 21 patients (32%), of whom nine had loss of normal cervical lordosis, 11 had right thoracic scoliosis, and one had dorsal hyper-kyphosis.n = 26) of the patients were evaluated as normal, 17.2% (n = 11) as borderline abnormal, and 42.2% (n = 27) as abnormal. According to the HADS-depression subscale, the scores of 54.7% (n = 35) of the patients were normal, 28.1% (n = 18) were borderline abnormal, and 17.2% (n = 11) were abnormal.In the HADS-anxiety subscale, the scores of 40.6% (n = 3) were borderline, and 82.4% (n = 14) were abnormal, and the HADS-depression scores showed that 11.2% (n = 2) of the patients were normal, 41.1% (n = 7) were borderline, and 47.1% (n = 8) were abnormal.Among the 17 patients with JFM, the HADS-anxiety scores revealed that all of the patients were in abnormal limits, 17.6% (n = 22) according to CSI. The presence of central sensitization among the 17 JFM patients was 70% (n = 12).Central sensitization was detected in 34.4% of patients (n = 28), emotional abuse , and sexual abuse . In the subgroup analysis of 17 patients with JFM, there was 64.7% (n = 11) emotional abuse, 64.7% (n = 11) physical abuse and 23.5% (n = 4) sexual abuse.According to CTQ, the presences of trauma were detected as physical abuse . All of the 17 patients diagnosed with JFM were female.There was no significant difference in age, duration of symptoms, and the scores of CSI, VAS, HADS-anxiety, HADS-depression and CTQ when the patients were compared by gender (p < 0.001) (Table p < 0.001)  Table . Figure p < 0.001), HADS-depression , VAS , and CSI . The results of multiple regression analysis for the CTQ are given in Table 2 = 0.601, p < 0.05), and the only significant predictor was VAS (p < 0.001). CSI was positively correlated with HADS-anxiety , HADS-depression , VAS , and CTQ . The results of the regression analysis for the CSI are given in Table A positive correlation was found between CTQ and HADS-anxiety . This suggests that JFM should be investigated, especially in chronic chest pain before evaluating the cause of pain as idiopathic.It is well-known that the most common cause of pediatric chest pain is idiopathic, and the most detectable are musculoskeletal causes, including costochondritis, muscle strain, trauma-related pain, and rib fracture. These causes usually result in shorter acute or subacute pain while idiopathic causes lead to chronic pain with a longer duration . In the Daskapan et al. compared 57 patients with non-cardiac chest pain to a healthy control group. The authors suggested that postural problems could cause non-cardiac chest pain and reported that especially a rounded shoulder, shortness in the pectoralis minor, and thoracic kyphosis played a role in pain . In our It was reported that anxiety is associated with nearly half of the cases presenting with non-cardiac chest pain, while depression is less commonly seen . KhairanJFM is a condition characterized by chronic widespread pain. Chest pain is also evaluated as part of the widespread pain index included in the diagnostic criteria of fibromyalgia. The patients with pain lasting longer than 3 months are evaluated in terms of diagnostic criteria . In prevCentral sensitization syndromes including fibromyalgia syndrome are used to describe a group of unexplained disorders without organic pathology . CentralThe HADS-anxiety and HADS-depression scores were higher in the JFM group than in the non-JFM group. Similarly, in the group with central sensitization, these scores were higher compared to those without central sensitization. It was reported that anxiety and depression are commonly seen in JFM. In a study evaluating 91 young adults with the diagnosis of JFM, anxiety was found in 70.3% and depression in 33.3% of patients . In the Child abuse is a condition that affects mental health and that is often under-reported, under-estimated, and over-looked condition, especially in the adolescent group. If not identified early, it can have chronic consequences . In the n = 11) emotional abuse, 64.7% (n = 11) physical abuse and 23.5% (n = 4) sexual abuse in 17 JFM patients. The CTQ values were also higher and in the central sensitization group compared to the patients without central sensitization. In addition, there was a positive correlation between CTQ and the scores of HADS-anxiety, HADS-depression, VAS and CSI. Therefore, we have considered that JFM cases with non-cardiac chest pain should be evaluated for central sensitization and child abuse.There was limited number of studies investigating relationship between fibromyalgia and childhood abuse in pediatric age group compared to adult fibromyalgia. In a meta-analysis, it has been reported that the association of fibromyalgia with physical and sexual abuse could be confirmed, although level of evidence was poor . In anotOne of the limitations of our study is the small number of patients with JFM. Prospective, controlled studies with a larger number of JFM cases are needed to better evaluate the investigated parameters  in this age group. Another limitation is that factors such as mental disorders including substance/alcohol dependence, environmental conditions such as family, peers, and school environment and other adverse childhood events  were not explored in this study.In adolescent patients presenting with non-cardiac chest pain, JFM in addition to postural/spinal disorders should be evaluated among musculoskeletal causes. JFM associated with central sensitization and child abuse, a previously overlooked cause, should also be investigated in this patient profile. The presence of central sensitization and/or fibromyalgia in children with non-cardiac chest pain may indicate child abuse.