Background: Epidural steroid injection (ESI) has been used in managing chronic radicular pain. Regarding various techniques of ESI, the synergistic effect of caudal ESI (CESI) on transforaminal ESI (TFESI) in chronic lumbosacral radicular pain in prospective randomized controlled trial has not been determined. Methods:  A total of 54 eligible patients with lumbosacral radicular pain were randomly allocated to undergo TFESI plus CESI (TC group) or TFESI alone (T group).  The effective response to treatment was predefined by at least a 30% reduced verbal numerical rating scale (VNRS) from baseline between group comparison and the functional outcomes as measured by improved Oswestry Disability Index by least 15 points from baseline. All participants were evaluated using a single blinded outcome assessor before the  procedure and at 1, 3 and 6 months after the procedure. P <0.05 was considered as statistically significant. Results:  Average VNRS reduced significantly from baseline after receiving procedure at 1, 3 and 6 months in both groups . The TC group exhibited more effective and showed significant pain relief compared with the T group at 3 months (P=0.01). However, no statistical difference was observed between sub group analysis in pain relief and insignificant difference between group comparisons of functional outcomes.Conclusions: A treatment combining TFESI and CESI showed significant pain relief over TFESI alone at 3 months. No effect was found concerning functional evaluation.Registration: Thai Clinical Trials Registry ID TCTR20171101002 01/11/2017F These inhibit the synthesis of prostaglandins, interrupting nociceptive c fibers and reducing edema surrounding the nerve root4.Chronic lumbosacral radicular pain (CLRP) is a common condition in pain and spine centers. Treatment is challenging among patients who do not respond to either medication or physiotherapy and epidural steroid injection (ESI) is one commonly used intervention to alleviate radicular symptoms9. The effectiveness of these three injected approaches has been shown. Related studies12 have reported that TFESI was more beneficial than CESI regarding pain relief in herniated disc or radicular pain13. However, one recent systematic review and meta-analysis revealed TFESI could be weakly recommended over CESI14. Furthermore, one retrospective study showed adjunctive CESI on TFESI significant relieved more pain than only TFESI15. Unfortunately, a prospective study has not been conducted of the additional effects of combining the epidural steroid approach. Consequently, this study aimed to compare the effectiveness of pain relief and functional outcome between additional CESI to TFESI and TFESI separately in chronic lumbosacral radicular pain in a prospective randomized study and also to investigate possible complications during injection.Different approaches of ESI are available, namely, transforaminal ESI (TFESI), interlaminar ESI (ILESI), and caudal ESI (CESI)TCTR20171101002).The study comprised a prospective, single center, randomized, double blind, active-controlled parallel group. Permission to conduct this study was granted by the Institutional Review Board of the Royal Thai Army Medical Ethics Committee and registered with the Thai Clinical Trials Registry on 11 November 2017  having a diagnosis of either symptomatology or physical examination correlated using magnetic resonance imaging (MRI) and unsatisfactory pain control with either medication or physiotherapy. The exclusion criteria comprised patients presenting significant neurological deficit or cauda equina syndrome, no absolute contraindications to intervention from MRI such as discitis or spinal infection, coagulopathy, psychiatric problem, pregnancy, language barrier or history of allergy to local anesthetics, triamcinolone and contrast media.All patients were interviewed and physically examined by only one pain physician. Pain characteristics were documented and randomly allocated in two groups equally using a randomization with block size of four from a computer-generated table and concealed envelope. The random numbers were kept sealed and opened by a nurse anesthetist uninvolved in this study. Those in the TC group received CESI in addition to TFESI, and the T group received only TFESI. All participants and one nurse anesthetist, trained as outcome assessor were blinded to the study group.The intervention was performed as a day surgery using local anesthesia. The treatment level determined for supraneural transforaminal approach was based on clinical symptoms correlating with MRI. All patients were placed in the prone position, then pulse oximetry and noninvasive blood pressure were monitored. The lower back and buttocks areas were cleaned using sterile fashion technique.o ipsilateral to the affected side and 0 to 10o cephalo-caudad tilt until aligned with the superior vertebral end plate. The needle entry points were identified and the skin was infiltrated with 4 to 6 mL 1% lidocaine. A Quinke needle   was inserted in the direction of the radiation beam. The supraneural transforaminal technique was performed, and the tip of the needle was placed below the pedicle and within the upper half of the intervertebral foramen in the lateral image. Then 0.5 to 1 ml of nonionic contrast media  was injected via extension tubing to confirm the needle’s location at the target area under real time fluoroscopy. The caudal epidural space was identified using fluoroscopic guidance in the lateral position and then a 16-gauge introducer Touhy needle  was inserted through the sacral hiatus into the caudal space and an epidural catheter was inserted using Touhy needle. Then 0.5 to 1 ml of nonionic contrast media was injected via epidural catheter  under real time imaging to confirm the desirable vertebral level and covered target site on both groups as shown inA C-arm fluoroscope  was adjusted and rotated obliquely 20 to 2516 between group comparisons. The secondary result was functional outcome, measured by improved Oswestry Disability Index 17 at least 15 points from baseline. All participants were completely supervised and evaluated by blinded outcome assessor before the procedure, and then subsequently at 1, 3 and 6 months after procedure when attending the outpatient department of PMK Pain Treatment Center.The primary outcome was an effective response to treatment, predefined by at least a 30% reduced verbal numerical rating scale  from baselineet al.12. The probability of significantly reduced pain from TFESI was 0.90, whereas the probability of significantly reduced pain from CESI was 0.545. The result indicated 24 patients were required for each group to reach a significance level of 0.05, the power of study was set at 80%, and we added 10% more for loss to follow-up. The final number of participants totaled 27 per group. All analyses and summaries were performed withStata, Version 13/SE . AP value <0.05 was considered statistically significant. Descriptive statistics for continuous variables was presented as mean and standard deviation (SD) for sufficiently normally distributed variables. For nominal data, absolute and relative frequencies were displayed for each category. Independent t-test and Chi-square test were performed to compare the differences between groups in continuous variables and categorical variables, respectively. Multilevel mixed linear regression was performed to compare the Verbal Numerical Rating Scale (VNRS) and ODI Questionnaire change over the study period between both groups. A random intercept for the patients was included in the model to account for the cluster structure of the data (two-level models).The sample size was calculated based on the related study of Ploumis A18. Mean baseline VNRS was high in both groups; 74.8 ± 16.8 and 69.6 ± 15.1 in the T and TC groups, respectively.In total, 54 eligible patients were enrolled and allocated in equal groups of 27. Two participants were more excluded due to wrong allocation from progressive weakness and scheduled for surgery in the T group. Consequently, 25 patients remained in the T group and 27 in the TC group as shown in18. Moreover, average ODI was significantly improved from baseline at 1, 3 and 6 months in both groups. Nonetheless, no significant difference was found in average ODI over the study period between group comparisons (p=0.235) as presented in18.Overall, average VNRS was significantly reduced from baseline after receiving the procedure at 1, 3 and 6 months in both groups . However, the study showed significant differences between group comparisons at 1 and 3 months , respectively) as shown in18. This study showed the TC group exhibited more patient responses to the procedure and a significant difference than T group at 3 months follow up (p=0.01). However, there was no significant difference between group comparison in subgroup allocation (p>0.05), as shown in18 . Interestingly, the TC group were more satisfied with the treatment outcome in spondylolisthesis and failed back surgery syndrome at 3 months, although not statistical significance .The number of patients, responding to treatment, was measured by decrease in VNRS of 30% or greater from baseline at each follow-up period, as presented in18.Functional outcome assessed by the number of patients with improved ODI at least 15 points at each follow-up period showed no significant difference between groups, classified by either radicular symptoms or etiology as shown inAdditionally, no serious complications, such as neurological deficit, was reported during the course of the study.This constituted the first prospective study to compare clinical outcomes of combined CESI to TFESI (TC group) and TFESI alone (T group) to alleviate chronic lumbar radicular pain.20. Accessing the epidural space of the supraneural TFESI is relatively difficult in a severely degenerated and narrowed foramen21. Furthermore, the injected volume of lumbar TFESI is likely to influence the results. Prior studies have reported that larger injected epidural volumes provide effective pain relief22 and a larger injected volume can lavage waste products from the epidural space, reducing the abnormal signal of the offending nerve and increasing blood flow to the ischemic nerve23. Desaiet al.24 confirmed that the more vertebrae covered by the injected volume the better the outcome, and Furmanet al.25 commented that a larger injected volume was needed for failed back surgery patients. Unsurprisingly, the TC group showed trending toward more pain relief in spondylolisthesis and failed back surgery syndrome.This study showed combined CESI with TFESI provided more effective pain relief than TFESI separately at 3 months. Moreover, a trend was shown for higher pain relief in the TC group among spondylolisthesis patients  and fail back surgery syndrome (5 of 6 patients in the TC group compared with 1 of 5 the patients in the T group) at 3 months in subgroup allocation, without significant difference in which prior studies reported the mechanism of radicular pain in spondylolisthesis was usually from mechanical compression resulting in inflammatory changes in the enclosing nerve root and venous and arterial flow disability22Unfortunately, this study showed the TC group experienced more significant pain relief than the T group alone at 3 months this might have been from the effect of combined techniques peaking at 3 month, then it might have gradually worn off from steroid’s action, instability and the return of softened epidural adhesion and fibrosiset al.26 found epidural steroid injection plus lidocaine proposed insignificant benefit as compare with lidocaine separately in 400 patients who had lumbar central spinal stenosis and moderate to severe leg pain. On the other hand, they demonstrated interlaminar or transforaminal approaches which were not exactly same techniques as this study.However, Friedly JL15. In contrast, this study showed no significant pain relief between the 2 groups from herniated disc in subgroup allocation, for which demographic data of our patients with herniated disc showed lower average ages  than a related study  in which younger patients might have received greater benefit from steroid injection in accordance with Parket al.27 showing younger age produced a better response from TFESI. However, no significant difference was observed. Moreover, this study investigated just mild degree herniated disc such as mild unilateral paracentral disc herniation or mild foraminal stenosis and mild degree of spinal stenosis in which only the TFESI technique was sufficient to alleviate pain. Furthurmore, this study injected a larger volume in the T group (3.0 ml) compared with 1.5 ml in the study of TFESI by Kircelli Aet al.15 in which a larger injected volume could cover more pain generators across multiple levels of the spine in accordance with Furmanet al.29Recently, a retrospective study reported combined caudal and TFESI in herniated disc provided more significant pain relief and improved patient satisfaction than only TFESI at 1 year29, while Kanget al.30 revealed no significant difference between 10, 20 and 40 mg of triamcinolone at 1 week in TFESI for disc herniation with lumbosacral radicular pain. Unsurprisingly, this study also showed no significant difference in herniated disc concerning different dosages of corticosteroid between the 2 subgroups analysis.In addition, this study postulated that synergistic anti-inflammatory effect from the double dose of steroid in the TC group may have conferred better pain relief. However, one related study reported 40 mg was as effective as 80 mg of methylprednisolone in TFESI for lumbar radicular pain33, which might have limited the efficacy of the procedure. However, many common problems are involved in chronic low back pain. Secondly, electrodiagnosis was not performed in this study. Nonetheless, electrodiagnosis may have demonstrated false-negative findings, as demonstrated in a similar publication which showed 40 to 85% sensitivity depending on the referral range35. Thirdly, the study did not verify anterior or posterior epidural space of contrast flow which might have affected the efficacy of the result. Fourthly, this study included a small sample size for subgroup allocation which likely underpower analysis and might not have been able to detect differences between subgroups. A larger sample size in each etiology should be demonstrated in further study. Fifthly, this study provided two different approaches, which could be increase costs of procedures. Therefore, the higher volumes should be considerated if the effective result was occurred from higher volumes. Sixthly, some patients had bilateral radicular pain but only one side that more severe pain were provided in T group which might have effected for the result. Seventhly, this study did not collect exactly the duration of pain that can have huge effect on outcome as Bicketet al.36 ‘s propose. However, this study included only patients who had history of lumbosacral radicular pain more than 6 months. Lastly, we did not determine whether combination effect of oral medication, physiotherapy and placebo effect which might be effect for the result.Our study had several limitations. Firstly, we demonstrated radicular pain from symptomatology and physical examination, for which the source of pain may have overlapped the pain referred pattern from the zygophysial joint, sacroiliac joint pain or enclosing soft tissuesThe additional effect of CESI to TFESI was more effective than TFESI separately at 3 months with no neurological deficit.https://doi.org/10.6084/m9.figshare.12320846.v218Figshare: data_epidural_04042020.xls.36)- data_epidural_04042020.xls This project contains the following extended data:https://doi.org/10.6084/m9.figshare.1236149038Figshare: CONSORT checklist for ‘Effect of supraneural transforaminal epidural steroid injection combined with caudal epidural steroid injection with catheter in chronic radicular pain management: double blinded randomized controlled trial’ The manuscript seems improved and I'm satisfied with the revision, but I would recommend an English language edit.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?PartlyAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:NAI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Thank you the authors for thoughtful responses. The revised article which states 30% or more pain relief as "clinical significant "makes the results more appropriate. Additionally, the authors have added two fluoroscopic imagings which help to determine the deposition of injectate.  I appreciate the version 2 of this manuscript, making it more comprehensive and useful.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?PartlyAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Anesthesiology and Pain managementI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. I agree with your revision. Clinically meaningful pain relief is defined as at least 30% reduction in pain.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Anesthesiology, Pain managementI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. General Comments:This study is very relevant to today's practice and important for patients' wellbeing and continuous healthcare for low back pain with radiculopathy.Overall coverages and discussion are appropriate.The main limitation for this study is the imaging that showing the flow of contrast which determine of the deposition of steroid as well as the outcome.Introduction:Adequate and covering the area of research.Methodology:The selection of participants are adequate.I am totally agreed with the selection of a common cause of low back pain in this study.  Results:The table and the analysis of the result are adequate.Discussion:The coverage of the discussion and suggestion are adequate.However, my concern with the selection of participants who is inexperienced without comparing the senior student may affect this study's strength.References:AdequateOthers:This is a good and practical study and should be encouraged to do it multicenter. This is a very interesting study and can give us options if we may encounter partial or temporary relief with one approach. The limitation of this study is that we can confirm that limited outcome is it due to mechanical that reduces the flow of injected since no contrast was viewed prior to injection.Further reading 1Rashmi Datta, KK Upadhyay. A Randomized Clinical Trial of Three Different Steroid Agents for Treatment of Low Backache through the Caudal Route. MJAFI 2011; 67: 25-33 et al. Comparison of Pain Score Reduction Using Triamcinolone vs. Betamethasone in Transforaminal Epidural Steroid Injections for Lumbosacral Radicular Pain. Am. J. Phys. Med. Rehabil. 20152McCormick Z et al. Factors associated with the outcome of transforaminal epidural steroid injections. Korean J Anesthesiol. 2008; 55(3): 298-304.3Tae Kyu ParkIs the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:NAI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Thank you for your review and comment. We already edited  and add more contrast flow picture as new version Best regards Authors 1The primary outcome of this study was an effective response to treatment, predefined by at least a reduced verbal numerical rating scale from baseline. If the cut-off point for the percentage of pain intensity difference was 33%, the primary outcomes may be changed. A 33% pain intensity difference is a standard of the clinically important difference in pain outcome measures.Figure 2 and figure 3 were alternated figure legends.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:pain managementI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Thank you for your review and comment. We already edited as new version Best regards Authors The authors conducted an interesting randomized study comparing transforaminal epidural steroid injection (TFESI) to TFESI combined with caudal ESI. The methodology and flow of the study were organized. The analysis was properly done and results were clear.  However, figures 2 and 3 are wrongly placed. The legends of figures state they are average verbal numerical rating scale (VNRS) and average Oswestry Low Back Pain Disability Index (ODI) respectively, while the Y-axes show ODI and VNRS, respectively. The discussion is well written. Nevertheless, I think it would be fair if the two groups received the same total dosage of steroid, although many studies did show that two different doses of steroids did not make any differences. Another limitation of such a study, is that the patients were not blinded from their study groups would be a higher placebo effect in the group that received combined injections.  Additionally, it would be beneficial if the author had studied comparing cost-effectiveness between these two study groups.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?PartlyAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Anesthesiology and Pain managementI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Thank you for your review and comment. We already edited as new version Best regards Authors The authors have performed a small, randomized trial comparing transforaminal epidural steroid injection (TFESI) to TFESI plus add-on caudal ESI. This is an interesting concept, there are not many randomized trials that compare add-on therapy . I enjoyed reading this and feel it would be a welcome addition to the literature.Introduction:Introduction, para 1: Steroids also suppress ectopic discharges of injured nerves, and may enhance the washout of inflammatory cytokines. This is eloquently noted in the discussion but should be noted at the beginning of the introduction as well.et al. studies for neuropathic medications), the results are usually not even additive.The authors use the term synergistic incorrectly. Synergistic would be 20% + 20% = 50%, but while 2 treatments may afford better results than a single one .  The authors should, therefore, provide a rationale as to why the combination should work better (the background on the literature is otherwise focused and to the point). Please consider providing objectives in the ‘introduction’ .Methods:I actually like the fact that there was no minimum pain score, as this is always subjective and when a minimum is employed, patients often end up skewed towards the cutoff .On a similar note, I also appreciate that patients with both a herniated disc and spinal stenosis. Were there any differences in outcomes?Many patients with radicular pain have bilateral symptoms. If this were the case, how did the investigators choose what side to inject? Or were these patients excluded ?Why did a nurse anesthetist assess outcomes? Was sedation used (please mention)?et al. NEJM, FDA-endorsed CLEAR study) to detect a difference between an ESI and a sham injection, so comparing 2 different ESI should require even more. Yet, the authors have shown a difference.Although the authors performed a power analysis, the study is likely underpowered, as well-designed studies now enroll several hundred people (see FriedlyPlease consider mentioning the randomization block size.The study had excellent retention (few lost-to-follow-ups), but please note how missing data were handled in the ‘statistical analysis’ section.Results:> 50% pain relief, but the IMMPACT guidelines state that 30% or more relief is ‘clinically meaningful’, so most pain studies now use that cutoff as a positive outcome. According to a review by Bicket MCet al. in Pain Pract 2017, an even lower percentage of pain relief seems to predict satisfaction in most patients. So you might consider showing the proportion of people who also obtained> 30% pain relief.I agree with one categorical outcome beinget al. AQUARIUS.. Reg Anesth Pain Med 2018). Please note the duration of pain for the groups.Duration of pain is a really important clinical variable that can have a huge effect on outcome .Discussion: - in general, well-written and focused.There are 2 possible reasons that warrant mention as to why a difference was shown. One is that the combination group received a higher dose of steroid and local anesthetic (if there had been a group that received a higher dose of steroids by one route as a control that would have formed another control and answered questions). However, there are half a dozen studies that compare 2 different doses of steroids and nearly all have found no difference. The second reason is that the group that received both injections had greater expectations, and therefore had a higher placebo response rate. Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?PartlyAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Pain MedicineI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Thank your so much Dr.Cohen for your review and comment.We already revised the manuscript in Version 2 and have changed the definition of pain relief from 50% to 30%, the conclusion was changed in the subgroup analysis.All of nurse in our clinic are nurse anaesthetists. Therefore, only one nurse anaesthetist was trained to evaluated the outcome.  However, the patients had not been sedated.Furthermore, we performed other answers in the revised version.Best regardsAuthors


Migraine is a recurrent, disabling neurovascular headache disorder. The patient's quality of life can be severely impaired by migraine attacks. Stellate ganglion block (SGB) can be used to relieve pain in the head, neck, and upper extremities. In the present cases, we performed SGB in 2 patients with migraine that responds poorly to drugs.Patients 1 and 2 suffered from chronic, bilateral pulsating headache, accompanied by nausea and vomiting. Patient 1 presented with headache of 8 on the visual analog scale (VAS), and 37 on the migraine disability assessment (MIDAS). Patient 2 reported headache of 7 on the VAS, and 32 on the MIDAS.The patients were diagnosed with migraine without aura based on the International Classification of Headache Disorders version 3.Patient 1 was treated with bilateral SGB every week for a month and then every month for 3 months. Patient 2 received bilateral SGB every 2 weeks for a month and then every month for 3 months.Four months after SGB, patient 1 reported pain intensity of 4 on VAS and 6 on MIDAS and patient 2 rated pain intensity of 3 on VAS, and 6 on MIDAS, respectively.The SGB can be an effective option to improve headache-related disability and relieve pain intensity in the patients with refractory migraine. It was reported that migraine headache depends on an altered excitability or dysfunction of the brain state by the activation of the trigeminovascular pathway. Migraine is typically a pulsating and throbbing headache that can be unilateral or bilateral, accompanied by nausea, vomiting, muscle stiffness, and increased sensitivity to light, noise, smell, and touch. In addition, before a migraine attack, warning signs (premonitory symptoms) such as fatigue, mood change, food carving, and increased yawning and aura often occur; are derived from the hypothalamus, brainstem, and cortex.,3Migraine is a common, recurrent, disabling neurovascular disorder initiated by many trigger factors, such as stress, sleep deprivation, hunger, prolonged sensory stimulation, and hormonal variation. The MIDAS questionnaire is a simple, self-administered questionnaire consisting of 5 questions. MIDAS has been proved to be highly reliable and correlated with clinical determination regarding the need for medical treatment.Patients’ quality of life can be severely impaired by migraine attacks. Migraine Disability Assessment (MIDAS) questionnaire was designed to measure headache-related disability over a 3 month period.,7 In addition, SGB is indicated for the treatment of pain disorders such as herpes zoster and complex regional pain syndrome.,9Stellate ganglion, a sympathetic ganglion, innervates the head, neck, and upper extremities. Stellate ganglion block (SGB) improves blood supply to the ipsilateral neck, and upper extremities, which is effective to treat vascular insufficiency.In the present study, we found that bilateral SGB is effective to reduce pain and improve MIDAS scores in 2 patients with migraine. Consents for the publication of this report were obtained from all patients.22.1A 48-year-old female presented with a 15-year history of migraine. The headache was bilateral and pulsatile over the frontal and temporal regions, accompanied by nausea and vomiting. The frequency of pain attacks was about 3 times a month and the duration of pain was 48 hours. The pain worsened around the patient's menstrual cycles. The patient felt fatigue and dizziness 1 day before the onset of headache. The patient was diagnosed with migraine by a neurologist and was taking a daily dose of propranolol 10 mg, naproxen 500 mg, acetaminophen 1200 mg, and ergotamine 1 mg. Despite these medications, pain intensity was 8 using visual analog scale (VAS), and MIDAS score was 37 . It is considered that the patients with MIDAS score 6 or higher need medical care. Many drugs, including beta blockers, antidepressants, nonsteroidal anti-inflammatory drug, ergotamine, and triptan have been used for prevention or management of migraine. However, these medications cannot often alleviate migraine. In the present case, despite of medications, the MIDAS scores of patient 1 and 2 were 30 and 37, respectively.Migraine can severely impact patient's quality of life. The MIDAS questionnaire assesses headache-related disability over 3 month period. This is regarded as a useful tool to improve communication between physicians and patients and to identify headache patients with significant treatment needs. SGB produces several actions. First, it increases blood supply by sympatholytic effect in its sphere of innervation.,7 Second, SGB inhibits neuronal connections between the stellate ganglion and the brain, which may produce therapeutic effects in various diseases, such as post-herpetic neuralgia, post-traumatic stress disorder, hot flashes and sleep disturbances in breast cancer survivors.,16,17 In addition, SGB is reported to be effective for treatment of tension headache and headache following post-traumatic stress disorder.,19 The exact mechanism of analgesic action of SGB in these disorders remains unclear. SGB decreases electroencephalogram indices of arousal in animal study and has sedative effects in healthy volunteers.,21 This action mechanism of SGB includes restoration of the normal melatonin rhythm. It was reported that patient with migraine have low level of melatonin. Melatonin is effective to prevent migraine by preventing nitric oxide synthesis, inhibiting calcitonin gene-related peptide release, and antagonizing glutamate-induced excitotoxicity.,24 In addition, stress is often cited as a trigger for migraine. In response to stress, sympathetic nerve activity increases, leading to a release of several neurotransmitters associated with pathogenesis of migraine such as dopamine, and prostaglandin. For instance, the excessive dopamine level leads to nausea, vomiting and yawing and the increase of prostaglandin augments pain sensitivity and inflammation in migraine patients.,26 In the present cases 4 months after SGB, patient 1 reported pain intensity of 4 on VAS and 6 on MIDAS and patient 2 rated pain intensity of 3 on VAS, and 6 on MIDAS, respectively. Therefore, we presumed that SGB is effective to improve migraine by restoring normal level of melatonin and decreasing sympathetic activation with response to stress in patient with migraine.The stellate ganglion, a sympathetic ganglion innervating the head, neck, and upper extremities, extensively connects with the cerebral cortex, hypothalamus, amygdala, and hippocampus. Ultrasound-guided peripheral nerve block improves the efficacy of the intervention by direct visualization of the best site for the injection and helps avoid the damage to blood vessels and nerves.,29 In addition, the volume of the injectate can be reduced.,29 In the present study, the left SGB was performed 30 minutes after the right SGB with lidocaine 5 mL under ultrasound-guidance and there were no side effects such as hypotension and bradycardia.SGB can decrease hemodynamics.In conclusion, SGB can be an effective option to improve MIDAS scores and pain intensity in patients with refractory migraine. Further prospective controlled studies are needed to define the therapeutic role of SGB in managing migraine patients.Data collection: Joonhee Lee.Review and editing: Younghoon Jeon.Writing – original draft: Suyoung Moon.


Low back pain (LBP) and comorbid post-traumatic stress symptoms (PTSS) are common aftertraumatic injuries, and a high level of PTSS is associated with more severe pain andpain-related disability. Few randomised controlled trials (RCT) exist targeting comorbidPTSS and chronic pain, and only one has assessed the effect of SomaticExperiencing®.The aim of this study was to assess the effect of Somatic Experiencing® (up to 12sessions) + physiotherapeutic intervention (4–8 sessions) (SE+PT) compared with thephysiotherapeutic intervention alone (4–8 sessions) (PT) for pain-related disability inLBP with comorbid PTSS.n = 114) were recruited consecutively from a large Danish Spine Centre.Patients were randomly allocated to either SE+PT or PT alone. Outcomes were collected atbaseline before randomisation, 6 and 12-month post-randomisation. The primary outcomewas pain-related disability as measured with the modified version of the Roland MorrisDisability Questionnaire at 6-month post-randomisation. Secondary outcomes were PTSS,pain intensity, pain-catastrophising, kinesiophobia, anxiety and depression.The study was a two-group RCT in which participants (No significant group differences were found on any of the outcomes at any timepoints.Both groups achieved a significant reduction in pain-related disability (20–27%) asmeasured by the Roland Morris Disability Questionnaire at 6 and 12-month follow up.Also, both groups achieved a small reduction in PTSS.Although significant effects were achieved for both groups, the additional SEintervention did not result in any additional benefits in any of the outcomes. While it is well known that neck pain is common after motor vehicle collisions (MVC), it isless well known that low back pain (LBP) is equally as common as neck pain, with aprevalence of 37%  , Andersen et al.  assessedn = 44). Only theCBT group achieved a large significant reduction in PTSS. However, none of the groupsexperienced significant reductions in pain. The final trial by Dunne et al. (n = 26) on whiplash-associated disorders investigating the effect oftrauma-focused CBT compared with a waitlist condition. In contrast to Andersen et al.  would reduce pain-related disability compared with thephysiotherapeutic intervention alone (PT) at the 6-month follow up. Secondly, compared withthe PT alone, we hypothesised that the additional SE intervention (SE+PT) would reduce allsecondary outcome scores at the 6-month follow up .1.1.1.n = 114) were recruited consecutively from a large Danish spine centre in theRegion of Southern Denmark, between January 2016 and December 2017. Patients with LBP wereincluded in the study if they were between 18 and 70 years of age and had experienced atraumatic event (MVC or injury) within the last 5 years  and all participants gave written informed consent before study entry. Thestudy was funded by the Danish Victims Fund, which has been set up by the DanishParliament, with the objective being to fund projects and activities that provide furtherknowledge of, or support for, victims or groups of victims of crimes and road accidents.The funding body has not played any role in the study design or the collection, analysisand interpretation of data.1.2.Patients were randomised using random permuted blocks of six. Randomisation procedureswere administered by a project nurse, blinded to treatment assignment. Patients wererandomly allocated to either: Somatic Experiencing® (SE) plus physiotherapeuticintervention (PT) or PT alone, and the interventions were initiated within 2 weeks afterrandomisation. Primary and secondary outcomes were collected at baseline beforerandomisation (T0), 6 (T1) and 12-month (T2) post-randomisation. The study statisticianwas blinded to treatment allocation and the patients were blinded to the hypotheses.1.3.Both intervention groups (SE+PT and PT) received the same physiotherapeutic intervention,as described below. However, one group received the additional SE intervention (SE+PT). Inthis group, both the PT intervention and the SE intervention were delivered as weeklysessions, most often within the same week but never on the same day. For pragmaticreasons, sessions were scheduled to best suit the patient; however, within the timeframeof 12–16 weeks in total.1.4.The PT intervention was an individualised functional treatment with the aim being toimprove daily functioning. The intervention was based on guided exercises for LBP, andexposure to feared movements or exercises. The intervention did not apply any manualtreatment, such as massage or manipulations of muscles and joints. The intervention wasdelivered in 4–8 weekly sessions, each approximately ½-1 hour, by physiotherapists in thecentre and according to the European guidelines for the management of chronic LBP withseveral years of experience in SE and pain management. The SE intervention was deliveredaccording to the nine-step model as outlined by Peter Levine Levine, . The nin1.6.The primary outcome was pain-related disability as measured with the modified version ofthe Roland Morris Disability Questionnaire  These models make it possible to deal efficiently withmissing values due to dropout, assuming the dropout pattern is missing at random (MAR).Thus, all available data were used, and intention-to-treat analyses applied.Fixed effects included time point and a group × time-point interaction term, where weadditionally adjusted for sex and age. Because participants were randomised to eitherintervention or control group, the interaction tested for the existence ofgroup-by-time-point interaction.We included a random effect in the model for each subject, allowing each subject to havetheir individual intercept. For every outcome, the necessity of a random slope was testedand included in cases where it represented a significant improvement in the model .d as follows:small = 0.20, medium = 0.50, and large = 0.80. According to the literature, the minimalclinically important difference (MCID) in pain-related disability was determined to be a30% reduction on the RMDQ compared with baseline  and SPSS version 26 .2.2.1.In total, 114 patients were included in the analysis. Of those, 66% were females. Themean age was 41 years (SD = 11.8). The mean number of years with chronic LBP was 3 years(SD = 3.74). The majority of patients had experienced multiple traumatic events; however,the most common index traumas reported were traffic accidents (47.8%), physical assaults(52.2%) and work-related accidents (39.3%).p > 0.05) between completers andnon-completers in age or on any of the primary or secondary outcomes atbaseline.The unadjusted means and SD for all outcomes and timepoints for both groups are shown inThe mean number of SE sessions delivered was 10 (SD = 3) delivered within 12–16 weeks.The PT intervention was delivered within the same timeframe and all patients receivedbetween 6 and 8 sessions, each of ½-1 hour.2.2.Firstly, we investigated whether the outcomes changed over time, and secondly, whetherthe two treatment groups differed at any timepoint. The mixed-effects models of the groupdifferences over time are shown in p< 0.001) and from baseline to the 12-month follow up (T2)  was significant. There was nodifference detected between T1 and T2 .There was a significant main effect of time on the primary outcome, pain-relateddisability, as measured by the RMDQ. Contrasts revealed that the decrease in RMDQ frombaseline to the 6-month follow up (T1) , this improvement diminished, with no significantdifference from baseline to T2 . Together, these trajectoriesdemonstrate that any improvement occurred in the time from baseline to first follow up(T1), with a stagnation between the first and second follow up (T2).Likewise, significant improvements from baseline to T1 were found on the secondaryoutcomes: PTSS (HTQ), pain intensity (NRS), pain-catastrophising (PCS), kinesiophobia(TSK), and anxiety (HADS-A), again with no differences from T1 to T2. There was noimprovement measured for depression (HADS-D) from baseline to T1  nor from T1 to T2 . Regarding anxiety, although thepatients improved significantly from baseline to T1  for eachoutcome, we found that specifically, for pain-related disability (RMDQ), the differencebetween the two groups was sizable, though non-significant ,with the SE+PT group having the lowest score, however this difference diminished by T2. No significant differences between groups were found for anyof the secondary outcomes at any timepoints, besides kinesiophoia (TSK), where a slightsignificant difference was found at T1  with the SE+PT groupscoring lower than the PT group. However, this difference decreased at T2 and becamenon-significant.Thus, the analysis revealed no significant interaction between group and timepoint on themain outcome and only one weaker interaction on a secondary outcome, namely kinesiophobia(TSK) at the first follow up. d = 0.75; 0.67). It corresponds to a22–27% reduction in pain-related disability and is considered more than a minimalclinically important difference (MCID) in the chronic sample in the current study , which is not above the MCID.In terms of effect sizes, the unadjusted mean differences for both groups, SE+PT and PTrespectively, revealed a moderate to large effect on pain-related disability (RMDQ) frombaseline to T1 (Cohen’s 3.The aim of the current study was to assess whether an additional SE intervention incombination with a PT intervention for comorbid PTSS and LBP would reduce pain-relateddisability compared with PT alone. It was hypothesised that the additional interventionwould have a larger effect on pain-related disability at the 6-month follow up, as well ason all the secondary outcomes.Contrary to expectations, there were no significant group differences on any of theoutcomes at any timepoints. Both groups achieved a significant reduction in pain-relateddisability at the 6 – and 12-month follow up, corresponding to 20–27% reduction inpain-related disability compared with baseline as measured on the RMDQ. The reduction inpain-related disability was slightly larger than what was achieved in the SE trial byAndersen et al. . Also, bSince self-report questionnaires are found to be over-inclusive compared with diagnosticinterviews assessing PTSD (Siqveland, Hussain, Lindstrøm, Ruud, & Hauff, Although PTSS are prevalent in chronic pain conditions, patients fulfiling all thediagnostic criteria for PTSD are less prevalent (Siqveland et al., 3.1.The current study has a number of limitations. The most important limitation is the lackof a diagnostic interview assessing PTSD. Hence, patients without a diagnosis of PTSD mayhave been included in the study. Although the SE, as an intervention, is not limited totreatment of patients with a diagnosis of PTSD, the inclusion of patients with moregeneral distress may have diluted the results. It is likely that the PT intervention alonewas sufficient for more general distress symptoms but not for patients meeting thecomplete diagnostic criteria for PTSD. Finally, the design does not allow for anassessment of the effect of SE alone compared with the PT intervention. Also, with nowaitlist control group, it is not possible to say whether the effect was due to any of theinterventions. For these reasons, it is not possible to draw any definite conclusionsabout the effect of SE for patients with LBP and comorbid PTSD. However, trajectorystudies have shown that the subgroup of patients with comorbid high levels of PTSS andpain tend to follow a trajectory characterised by little or no recovery in PTSS and painover time (Andersen et al., 4.The Somatic Experiencing® intervention did not have any additional effect on any of theoutcomes at any timepoint compared with the Physiotherapeutic intervention alone. However,the overall effect sizes were significant. In particular, the overall reduction inpain-related disability from baseline to the 6-month follow up was moderate to large andabove the MCID. Compared with the earlier SE study (Andersen et al.,


Chronic pain is a complex experience that has now become a major public health issue. This has prompted many researchers to study attention, understanding it to be a crucial factor that allows altering the experience of pain, while attributing considerable importance to sustained attention. Accordingly, the main studies in this field stress the importance of emotion regulation processes and emotions on the perception of painful stimuli and attentional processes themselves. Nevertheless, only a handful of studies have been found that directly study the relationship between these variables. Within this context, this article sets out to analyse emotional regulation processes, emotional variables (depression and anxiety), the experience of pain, and age on the ability to maintain the vigilance response in a sample of patients with chronic pain. This involved selecting a sample of 49 patients with rheumatoid arthritis and examining their performance in an ad-hoc sustained attention test. With a view to complying with the study’s main purpose, the participants were also assessed through the use of the following self-report measures: the Beck Depression Inventory (BDI-I); the Hospital Anxiety and Depression Scale (HADS); the McGill Pain Questionnaire, and the Difficulties in Emotion Regulation Scale (DERS). Linear regression analyses revealed a significant impact of the aging process on the performance times in the attention task. Likewise, age and depression recorded a significant correlation with the mistakes made during the task. These results suggest that higher depression levels and an older age might be related to a worse adaptation to pain management techniques based on attention processes, such as mindfulness. Chronic pain is a complex experience that has become a major public health issue not only because of its alarmingly high rate of occurrence , but alsSome authors now stress the importance of understanding this health issue from a biopsychosocial perspective , wherebyDespite the importance of this attentional component in the field of chronic pain, there are very few instances of empirical research that have addressed it directly . NeverthTherefore, this psychological construct “sustained attention” might have an implication in the clinical field, more accurately in the selection of the criteria for guiding a doctor’s choice of treatment. In this regard, we decided to conduct a broader analysis of the relevant literature looking for psychological variables that could interfere with the vigilance response. In general terms, the underlying mechanism by which this ability to uphold the vigilance response is affected by other variables is unclear. Nonetheless, according to posner's attentional model , 49 emotConsequently, it can be assumed that not only emotions, but one's abilities to successfully manage emotions, could also be relevant for the study of the attentional processes. Nevertheless, very few studies have considered the impact of emotion regulation mechanisms on attention or the experience of pain. In a recent review of emotion regulation in chronic pain , it was As regards the socio-demographic variables, there is evidence to show that ageing leads to a decline in the cognitive function –73. ManyHence the reason that our aim here was to analyse the relationship between age, depression, anxiety, rating of pain and the capacity for emotion regulation, and their predictive capacity in an ad-hoc visual task involving sustained attention, given the proven relationship between these variables and the maintenance of attention according to the main theoretical models mentioned earlier , 48, 49.This study involved a sample made up of a total of forty-nine patients diagnosed with rheumatoid arthritis. All the participants had to have been experiencing pain for more than six months to comply with the criteria of the Spanish Pain Society—Sociedad Española del Dolor (SED) for chronic pain, be aged over 18, and have volunteered to take part in the study. Those patients that had been diagnosed with an anxiety or mood disorder were discarded. Some of the participants were patients undergoing treatment at the Department of Rheumatology at the Hospital Clínico San Carlos in Madrid (Spain), while others were members of the Madrid Association of Patients with Rheumatoid Arthritis .The study was approved by the Research and Ethics Committee of CEIC Hospital Clínico San Carlos in Spain (record 15.531-E). Date of communication: 10 December 2015. Written informed consent was obtained from all participants after been informed about eligibility criteria, study procedures and study goal. Data collection regarding the consent was witnessed and supervised by the lead investigator. Only participants who completed data for all self-report measures listed below were included in the sample and taken into consideration for the statistical analyses. Those who did not meet the eligible criteria, as noted previously, were discarded and advised to seek psychological treatment.BDI-II. Beck’s Depression Inventory-II by Beck et al. The data were coded and analysed with version 25.0 of the SPSS statistical package. The study’s objectives were achieved by means of a stepwise multiple linear regression analysis. The independent or predictor variables were the emotional variables (depression and anxiety), DERS subscales, the scales of the pain rating index, age, and relevant sociodemographic to control their effect on pain, attentional processes or emotions, included as control variables . we tested the contribution of variables mentioned above to the explanation of variance for each one of the dependent variables, the number of mistakes made, and the overall performance time measured in milliseconds, as computed with the attention task. Before beginning the analysis, we ensured compliance with the conditions of normality, homoscedasticity, linearity, collinearity, as required for this type of analysis. The independence was fulfilled in the first set of regression analyses (Durbin-Watson = 2.390), while the data referring to the dependent variable on the mistakes made in our study’s test revealed that they did not fulfil this condition, as the Durbin-Watson statistic (1.264) did not fall within the recommended range (2 ± 0.5). The decision was nonetheless made to conduct the analyses for this dependent variable because it met all the other conditions required. SD ± 10.4), ranging from 28 to 77 years. The majority of the participants were female (75.5%). All 49 patients had been diagnosed with rheumatoid arthritis and the majority were taking a combination of different medical treatments for the pain , such as biological agents, FAMES, corticosteroids, anti-inflammatory or analgesic drugs. More than half were married , around a quarter were single , the rest were widowed , divorced  or separated . The majority of the participants were found to be employed , nearly one-quarter were retired , and the rest were students  or had other employment status . Many individuals reported medium incomes . Regarding their educational status, most of participants were attending primary or secondary school , another important part of participants was enrolled in some type of tertiary or vocational education . As regards the time elapsed since the first medical diagnosis,  of study participants had been diagnosed with rheumatoid arthritis between five and ten years or more than ten. and around one-third was single . The characteristics of the study participants, based on socio-demographics and relevant clinical variables are summarized in The mean age of study participants was 55 years (2 = 0.345), including the patients’ age as sole predictor  , with the independent variables listed above. The regression analyses conducted produced a statistically significant model  explaining around 34% of the variability in the data regarding total performance times in the attention task in our sample (Adjusted R ≤ 0.01) . The linIn a next set of regression analyses we tested the contribution of variables mentioned above to the explanation of variance in number of mistakes made in the sustained attention task. In the first step, the analyses revealed a model statistically significant  and it explained a total of 8.4% with age as unique predictor. With the addition of depression (ΔR² = 0.103) in the second step, the model increased its predictive power accounting for up to 17% of the explained variance , leading to a statistically significant improvement  in its capacity for predicting the dependent variable. Thus, the final model revealed by the analysis included two variables as a predictor of the participant’s number of mistakes made in the attention task, age and depression , obtainiThe present study investigated the relationship between psychological variables and attentional performance in chronic pain patients. To do this, a vigilance task made in an ad-hoc manner has been used to meet the proposed objectives. Results concerning the relationship between age and attentional performance show that age is a predictor variable of both the time the participants took to complete the task and the number of mistakes made. The relationship was direct and statistically significant in both cases, which means ageing is accompanied by an increase in the time required for completing the task and by more mistakes. Based on the literature reviewed, cognitive approach studies provided evidence that pain competes for limited attentional resources –92, and As regards the relationship between depression and the subject’s performance in the attention test, the results reveal a significant relationship with the mistakes made during the empirical task. The attention bias commonly appears in depression and, within this context, prompts the subject to focus their attention on the stimuli most closely related to a negative emotional tone . A possiIt was hypothesized that patients suffering anxiety should have performed worse in an attention performance task of this kind, our results have not found a relationship between this emotion variable and the results in the sustained attention task. As mentioned, other researchers have already contended that anxiety is associated with a greater hypervigilance of painful stimuli, a deficit in attention resources, or more difficulty in disengaging one’s attention in the presence of pain , 58, 95.Regarding the expression of pain (using the McGill questionnaire), we haven't found that this variable correlates with the mistakes made. At least in theory, we expected some sort of relationship between the rating of pain and the mistakes made in the task. On the one hand, some studies have shown an impairment in the performance of sustained attention tasks in the presence of pain –38. ThisThe results related to difficulties in emotion regulation, which were measured through the subscales of DERS, appear to be statistically irrelevant to predict the attentional performance. Although the role of emotion regulation and its relationship with attentional processes have been reported and some researchers suggested the importance of the difficulties in emotion regulation among patients with chronic pain –69, thesIn the light of the above findings, the results suggest that patients with depression or older age could face difficulties or impairment in sustained attention and, therefore, might be related to a worse adaptation to pain management techniques based on these attention processes, such as Mindfulness-Based Interventions (MBIs) . ParticuThere is another relevant issue to mention in connection with the fact that the sustained attention task was specifically designed for this study. To these it adds that there are very few studies that focus on sustained attention in the pain field. Accordingly, it is difficult to compare the findings in this study with the findings provided by other researchers. Future researchers should note issues such as the display times of images to patients with anxiety, the use of different self-report measures to evaluate emotion regulation processes or pain measures, or even the attentional task itself. These variables may change the results obtained in this study. Account must, therefore, be taken of these particular issues if we are to achieve more comprehensive results in future studies.Over the course of this research, we have encountered certain limitations or difficulties that need to be discussed. The sample of patients with chronic pain we have accessed (n = 49) is relatively small, restricting both the treatment of the data and the statistical analyses that have been conducted. Other researchers that have already studied sustained attention in relation to chronic pain have used samples of a similar size , 103–107In sum, this study helps to indicate the importance of emotion variables and their ability to modify attentional processes, although scholars have traditionally adopted the opposite approach. Despite its limitations, the study’s results suggest that variables such as age and depression have a negative impact on their ability to maintain the response of attentional vigilance, and indirectly provide evidence on the variables involved in the difficulty in disengaging from pain-related stimuli. In turn, the scarcity of studies on sustained attention fosters the need for its further understanding, which will enable us to discover whether there are more variables that may have an impact on its proper functioning. In the event that this information should exist, it could help to improve the interventions undertaken with these patients within the field of healthcare.S1 Data(ZIP)Click here for additional data file.


Introduction: The presence of a temporomandibular disorder is one of the most frequent causes of orofacial pain (OFP). When pain continues beyond tissue healing time, it becomes chronic and may be caused, among other factors, by the sensitization of higher-order neurons. The aim of this study is to describe psychological characteristics of patients with chronic OFP, their peripheral pain threshold, and electroencephalography (EEG) recording, looking for possible signs of central sensitization (CS).Materials and methods: Twenty-four subjects with chronic OFP caused by temporomandibular disorder were evaluated using the Research Diagnostic Criteria for Temporomandibular Disorders Axis I and Axis II. Pain intensity, catastrophizing, and presence of CS were assessed through self-reported questionnaires. Pressure pain threshold (PPT) was recorded in facial and peripheral sites; EEG activity was recorded during open and closed eyes resting state and also during the pain threshold assessment. Pain thresholds and EEG recordings were compared with a cohort of pain-free age- and sex-matched healthy subjects.Results: Patients with chronic OFP showed a significant reduction in their pain threshold compared to healthy subjects in all sites assessed. Greater reduction in pain threshold was recorded in patients with more severe psychological symptoms. Decreased alpha and increased gamma activity was recorded in central and frontal regions of all subjects, although no significant differences were observed between groups.Discussion: A general reduction in PPT was recorded in people who suffer from chronic OFP. This result may be explained by sensitization of the central nervous system due to chronic pain conditions. Abnormal EEG activity was recorded during painful stimulation compared to the relaxed condition in both chronic OFP subjects and healthy controls. Chronic pain is defined as pain that lasts for more than 3 months beyond the normal healing time . ChronicThis cross-sectional observational study describes factors related to chronic OFP and characteristics of patients in a cohort of 24 subjects with OFP due to TMD. This study has been reviewed by the Ferrara University Hospital Ethics Committees. All the procedures described have been carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. Written informed consent was obtained before all procedures. The study meets the STROBE Guidelines for observational studies .Patients who underwent rehabilitation for TMD at Ferrara Rehabilitation Hospital between January 2018 and January 2019 were assessed for eligibility. Age, sex, occupation, side and duration of TMD, past treatment for the TMJ, comorbidities, and medications were recorded. All subjects with a Numeric Pain Rating Scale (NPRS) of less than 3 in the 2 weeks prior to assessment or who took pain relief medication were excluded from the study . The othA medical doctor with an expertise in temporomandibular rehabilitation evaluated all subjects included in the study, following the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) Axis I .The RDC/TMD Axis II was used to assess psychological distress and pain-related disability . For theCatastrophizing has been defined as “an exaggerated negative orientation toward actual or anticipated pain experiences” and reflects a tendency to misinterpret or exaggerate apparently threatening situations . The PaiCentral sensitization was assessed using the Italian version of the Central Sensitization Inventory (CSI-I) . A CSI s2 flat circular tip used to apply pressure on subjects’ skin. A researcher was trained to apply increasing pressure of approximately 1 lb/cm2/s perpendicular to the skin using the dynamometer, following a protocol well described in literature  placed according to the 10–20 International System on a Fast’n Easy cap. A BrainAmp amplifier  was used to record EEG activity. All scalp electrodes were referenced to nasion and grounded at AFz during recordings. Horizontal and vertical eye movements were detected, respectively, with electrodes placed at the left and right outer canthi at Fp1 and below the eye at the non-painful side. The impedance of all the electrodes was kept below 10 kΩ. The EEG signals were recorded with a 1,000-Hz sampling rate with a low cutoff frequency of 0.1 Hz and a high cut-off of 1,000 Hz.Electroencephalography data were recorded during a 5-min resting state task with open eyes and a 5-min resting state task with closed eyes. Participants were instructed to stay relaxed and keep their eyes fixed on a cross in front of them during open-eyes recording. EEG was also recorded during the PPT assessment at the thenar eminence following the aforementioned protocol.The EEG data were preprocessed in MATLAB, using the EEGlab toolbox . A notchz-scores to improve comparability of PSD values across subjects and conditions. For the pain stimulus trials, the PSD was calculated from the 3-s window before reaching the sensory threshold. The z-score of the PSD was calculated for each electrode of each subject during each condition by subtracting by each PSD spectrum its mean and dividing by its standard deviation. For the statistical analyses, in order to minimize the number of comparisons, we calculated the average PSD in the different bands for clusters of electrodes centered around locations F3, C3, P3, and their homologous on the right side of the scalp. For each location, the PSD in each band was calculated as the average PSD in the band among the central and directly adjacent electrodes. To visually assess for relative differences in EEG activity due to the pain, the z-score PSD calculated during the pain stimulus trials was expressed as a percentage of the average PSD calculated from the resting state trials with the eyes open of all subjects. This choice for normalization was dictated by the fact that subjects had their eyes open during the pain stimulus trials. These data were then plotted for both groups for visual comparison.The spectral power in the different EEG bands  was calculated, during both resting state tasks, in the middle minute of the 5 min of each recording. The power spectral density (PSD) was calculated using Welch’s method, using 1-s windows and 80% of overlap over successive windows . The PSDDescriptive statistics were used for characterizing the sample. Continuous variables are reported as means and standard deviations, non-continuous variables as counts and percentages. Differences in PPT between patients with OFP and healthy subjects were assessed using the Wilcoxon rank-sum test due to non-normal data distribution. Patients with OFP were also divided according to intensity of pain, presence of psychological disorders, catastrophizing, and CS, and differences between groups were analyzed. Spearman rank correlation coefficient was used to measure strength and direction of association between psychological scores and self-reported questionnaires.z-score PSD of the OFP and the healthy subjects in the eyes open and pain stimulus conditions for each band and electrode cluster. This analysis was based on a two-way analysis of variance (ANOVA) test. The significance level was set to 0.05. All the statistical analysis on the EEG data was performed in MATLAB using custom-made scripts.This statistical analysis was performed using STATA 13.1 software with significance set at ?? < 0.05. Statistical analysis was also performed on the clustered EEG data. In this analysis, we compared the p < 0.05 for all the sites of assessment). Stratifying patients according to psychological assessment performed with RDC/TMD Axis II, we observed differences in PPT between groups of subjects with moderate or severe symptoms compared to those with low or mild; significant differences were recorded only for pain-related disability and depression   . No signz-score values for OFP and healthy individuals for both conditions are presented in z-score PSD values extracted during the PS trial and expressed as percentage changes with respect to the same values extracted during the EO trial. We observed a qualitative increase in the relative PSD values  in the gamma band in the controls that were localized mostly in the occipital region. In the patients, differently than the controls, increased values of PSD in the gamma band were instead observed in the central and frontal regions (C3/C4 F3/F4 electrodes) (The average PSD ctrodes) .In this observational study, we tried to describe features and clinical signs of people with chronic OFP due to TMD by comparing them with healthy controls. Our main finding revealed that people who suffer from this debilitating condition present a generalized reduction in PPT. This reduction in pain threshold was observed not only in facial sites but also in areas not involved by pathology, such as the upper trapezius and the thenar eminence. The phenomenon we observed may be due to CS, an increased responsiveness of nociceptive neurons to subthreshold input . FillingAgain from the OPPERA study, In our study, PPT was assessed in patients with OFP from a median time of 33 months. Chronic pain, critical in development of CS, has to last for more than 3 months to be defined as such . Pain laTo our knowledge, the current study is the first investigating EEG PSD during PPT assessment in people with OFP vs. healthy control subjects. In this study, we found no differences between patients and control subjects during resting and pain stimulus trials. Our results about the reduction in the EEG alpha power during pain stimulation, which we observed in both cohorts, had already been observed in literature, without distinction between phasic or tonic pain . We obseIncreased activity of the primary motor cortex (M1) area in people with chronic pain has been previously described in literature in various musculoskeletal conditions . A recenMovement dysfunction such as unnecessary protective behavior may justify our findings, when patients received a stimulus perceived as threatening. The primary motor cortex has already been target of brain stimulation treatment, with a positive impact on pain relief . AbnormaInterpretation of our findings is subject to several limitations. First, the small sample size does not allow us to confirm our results on PPT and EEG recordings. Even though CS may be hypothesized looking at our results, we cannot draw any definitive conclusion on the mechanism underlying sensitization of CNS. Second, interpretation of our results must consider the inclusion in our sample of fibromyalgia patients whose sensitivity to pain may influence their PPT.In a convenience sample of patients with OFP due to TMD we observed generalized reduction in PPT compared to age- and sex-matched healthy controls, not limited to facial sites. Generalized decrease of pain threshold seems to be linked to the severity of psychological symptoms such as depression and perceived health-related disability. Abnormal EEG activity was recorded during painful stimulation of non-painful sites of patients with OFP due to TMD. This observational study tried to identify potential signs of CS through the analysis of patients’ sensory and psychological profiles and brain activity. Our results can open doors to new strategies for the assessment and treatment of patients with CS due to chronic pain conditions.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ferrara University Hospital Ethics Committees. The patients/participants provided their written informed consent to participate in this study.AB, SS, SBu, and NB conceived the study and participated in its design. AB and SBo performed the instrumented and clinical data collections. AB and GS analyzed the data. AB, GS and SS interpreted the results, and drafted and revised the manuscript. All authors 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.


To characterize patients with chronic critical illness and identify predictors of development of chronic critical illness.Prospective data was collected for 1 year in the intensive care unit of a general hospital in Southern Brazil. Three logistic regression models were constructed to identify factors associated with chronic critical illness.Among the 574 subjects admitted to the intensive care unit, 200 were submitted to mechanical ventilation. Of these patients, 85 (43.5%) developed chronic critical illness, composing 14.8% of all the patients admitted to the intensive care unit. The regression model that evaluated the association of chronic critical illness with conditions present prior to intensive care unit admission identified chronic renal failure in patients undergoing hemodialysis  and a neurological diagnosis at hospital admission  as independent factors. In the model that evaluated the association of chronic critical illness with situations that occurred during intensive care unit stay, muscle weakness  and pressure ulcers  had the strongest associations. In the global multivariate analysis (that assessed previous factors and situations that occurred in the intensive care unit), hospital admission due to neurological diseases  and the development of pressure ulcers  had the strongest associations.The incidence of chronic critical illness in this study was similar to that observed in other studies and had a strong association with the diagnosis of neurological diseases at hospital admission and chronic renal failure in patients undergoing hemodialysis, as well as complications developed during hospitalization, such as pressure ulcers and muscle weakness. However, some patients who survive acute illnesses remain dependent on intensive treatment for long periods, and these patients constitute the chronic critical illness (CCI) population.,5 In addition, there is no uniformly accepted definition to characterize CCI.,6 The most commonly used definitions are the duration of the MV (> 14 or > 21 days) or the need for a tracheostomy.,7 For parameterization purposes, a consensus previously defined CCI as a condition in which MV is prolonged and lasts for at least 21 days.-10 Depending on the criteria used, patients with CCI constitute up to 15% of critical patients,,11 and considering the increase in life expectancy and the prevalence of CCI, this population is expected to increase over the years.-14It is difficult to confirm the evolution from the acute phase to the chronic phase of a CCI because there is no obvious reference that defines this transition.,16 The clinical complications resulting from these changes imply a greater need for home care or institutionalization and lead to frequent rehospitalizations, high rates of hospital and post-hospital mortality, and high direct and indirect costs.,17-22 Mortality after six months from hospital discharge exceeds the mortality of patients with the majority of malignancies, and the patients surviving with CCI infrequently return to social activities.Patients with CCI constitute a population with specific pathophysiological characteristics, and up to 20% of the population suffer from neuroendocrine, metabolic and neuromuscular alterations.,24,25 In addition to a better pathophysiological understanding of critical illness chronification, the epidemiological characterization of patients with CCI can aid in the planning and implementation of care protocols that prevent the development of devastating conditions in terms of morbidity and mortality. This information can also support health teams in adequately communicating with family members about the short- and long-term perspectives and in providing decision support on the continuation of advanced life support therapies.Despite its relevance, information on the epidemiology of CCI is still scarce.Given this context, the purpose of this study was to characterize the CCI population to identify predictors of development of the CCI state by comparing patients with CCI to other mechanically ventilated patients.This observational study was performed from August 2015 to July 2016 in a general intensive care unit (ICU) with 14 beds in a South-Brazilian public hospital without long-term care facilities. The hospital is a regional referral center for emergency, urgency, neurology, neurosurgery, oncology, orthopedic, traumatology, burn and transplant cases.Universidade da Região de Joinville (UNIVILLE), under opinion 1.153.723. Informed consent was voluntarily provided by all subjects included in the study .The research project was evaluated and approved by the Research Ethics Committee of All subjects older than 18 years who needed MV for more than 48 hours were included. Patients for whom a spinal cord injury or a neuromuscular disease  was the primary cause of hospitalization, patients who required emergency tracheostomy and patients who were diagnosed with brain death were not included; in addition, patients readmitted to the ICU, those with incomplete medical records and those who were transferred to another hospital were excluded. The subjects included were followed daily from the time of admission to the ICU to the time of hospital discharge or hospital death.,8,16 and/or tracheostomy to facilitate weaning of the MV, and the Control Group, which included patients who required MV for fewer than 21 days.The patients were divided into two groups: the CCI Group, which included subjects who required MV for at least 21 daysdelirium according to the Confusion Assessment Method for the Intensive Care Unit - CAM-ICU, pressure ulcers grade 2 to 4, upper gastrointestinal bleeding, candidemia, ventilator-associated pneumonia and sepsis - presumed or confirmed infection plus at least one organ dysfunction).The data were collected prospectively from the subjects' electronic medical records and transferred to a data collection form. The following information were recorded: demographic information ; previous comorbidities  disease); diagnosis related group at hospital admission and at ICU admission, including those related to the following neurologic conditions: ischemic and hemorrhagic stroke, subarachnoid hemorrhage, neoplasm affecting the central nervous system, and traumatic brain injury; procedures and medicines administered during the first 21 days in the ICU  scale, which classifies muscle strength by five grades: grade 0 (absence of movement), grade 1 (only a trace or flicker of a contraction), grade 2 (active movement only when gravity is removed), grade 3 (active movement against gravity), grade 4 (active movement against resistance), and grade 5 . and the Charlson index,28 were calculated on the first day of ICU admission. The Sequential Organ Failure Assessment (SOFA) was calculated on the first, seventh, fourteenth and twenty-first days of MV.The Simplified Acute Physiology Score 3 (SAPS 3)t test to compare means and the nonparametric Mann-Whitney U test to compare variables with asymmetrical distributions. Categorical variables were expressed as absolute and relative values and were compared using the chi-squared test. A p value < 0.05 was considered statistically significant. The odds ratio (OR) and 95% confidence interval (95%CI) were determined from the comparison of the two groups of subjects, which was performed to evaluate the impact of each variable on the development of CCI. All variables for which a significance level of p < 0.10 was obtained in the univariate model were selected to construct the three following models of multivariate analyses by logistic regression, considering CCI as a dependent variable: a global model, which assessed preexisting characteristics and those at admission to the ICU, as well as the characteristics developed during hospitalization; a model that analyzed only the preexisting characteristics and those at admission; and a model that exclusively analyzed the characteristics developed during hospitalization.The data were analyzed using MedCalc statistical software, version 16.4.3 . Continuous variables were expressed as means ± standard deviations. The Kolmogorov-Smirnov test was applied to assess the normal distribution of the data. We used Student's During the study period, there were 574 hospitalizations in the ICU, and 374 did not meet the inclusion criteria. Among the 200 subjects analyzed, 85 were included in the CCI Group because they required ventilatory support for at least 21 days (n = 56) and/or tracheostomy for ventilatory support weaning (n = 29). The other 115 subjects were included in the Control Group . The subversus 14.8%; p < 0.001), pressure ulcers , sepsis , and ventilator-associated pneumonia . The administration of muscle relaxants  and aminoglycosides  were also more common among patients with CCI than among the control individuals, and there was a trend towards greater use of corticosteroids among the patients .Based on the findings in The third model of multivariate analysis was constructed based on the findings of versus 5.1 ± 7.0 days; p = 0.02), in the ICU  and in the hospital . No differences were observed in ICU mortality  and hospital mortality . However, among the ICU survivors, the mortality was higher in the CCI Group than in the Control Group .Data on the length of stay and mortality are shown in Our findings reaffirm the high incidence of CCI that has been observed in other studies. For the patients with CCI, the most common reason for ICU admission was neurological diseases, and they had a higher frequency of health care complications, such as pressure ulcers and muscle weakness, than the Control Group.,27-30 We have to consider that longer ICU stays are more likely to result in more acquired issues, and we can assume that this is an inherent characteristic of the population of chronic critical patients classified by chronological criteria. The lack of a definition regarding these criteria led us to adopt the consensus definition for CCI, which is ≥ 21 consecutive days of MV; this definition is still one of the most used criteria and is suggested as the basis for future definitions. It is known that tracheostomy as a criterion of CCI can result in misreports for this population due to the selection of patients in situations different from those associated with chronic diseases.,8Patients with CCI present with complex and multifaceted syndromes that cannot be characterized by chronological and arbitrary criteria, such as the duration of MV and/or tracheostomy, and the syndromes should be additionally characterized by clinical and demographic aspects.,9,10,27 which may be explained by the greater severity of disease (mean SAPS > 60) observed in our population.,24Among the subjects admitted to our ICU, 14.8% were classified as having CCI. Despite the adoption of more selective criteria, the occurrence was close to the upper limit of the range reported by other authors (5% to 15%),,25,27,28 However, in our multivariate analysis, age was not identified as a predictor of CCI; the effect of age may have been attenuated by the high proportion of young individuals (less than 1/3 were over 65 years old), which is an expected characteristic in populations treated in trauma hospitals.For reasons inherent to the physiology of elderly individuals, the recovery of organic insults occurs more slowly; thus, old age is recognized as a risk factor for ICU chronification.,28Among the characteristics that existed prior to admission to the ICU, CRF as a comorbidity was one of the predictors of CCI. Chronic renal failure is a comorbidity that is associated with other diseases, such as diabetes mellitus and systemic arterial hypertension, with high degenerative potential that increases disease severity and morbidity.,16,17 Carson et al. proposed a multifaceted definition of CCI and suggested that neurological conditions such as ischemic stroke, intracerebral hemorrhages and cranial trauma should be included as criteria for CCI, in addition to prolonged MV, the need for tracheostomy and sepsis.,5 It is widely known that sepsis is a prevalent entity in the ICU, and it is associated with high morbidity rates.,31,32 Although it was not identified as an important factor in the multivariate analysis, the occurrence of sepsis, as a comorbidity that was developed during ICU stay, among patients with CCI was more than double that observed in the Control Group  , a major cause of in-hospital sepsis that is associated with prolonged MV, an intrinsic condition of patients with CCI.-35Neurological diseases at hospital admission constituted the diagnostic category most associated with CCI, corroborating the evidence showing that neurological diseases or abnormalities in the Glasgow coma scale score are the most frequently observed characteristics among patients with CCI.< 0.001) . The samRegarding the length of hospital stay before admission to the ICU, we detected a statistical tendency that presented it as a predictor of CCI in the multivariate analysis  . The len a value close to that observed in our subjects (68.2%). Assuming that there is no clear cutoff for the CCI definition and that, for example, some authors consider 14 days as the appropriate cutoff, we might consider that some variables such as pressure ulcers are consequences (even if developed within 21 days) rather than predictors of a chronic condition.Among the characteristics associated with the CCI developed during ICU admission, we identified pressure ulcers and muscle weakness as independent factors . Patient The factors most involved in its occurrence are systemic inflammation, malnutrition, uncontrolled glycemia, sepsis, sedatives, corticosteroids, aminoglycosides, neuromuscular relaxants, immobility and prolonged MV. Many of these factors were confirmed in our results, reinforcing the external validity of our findings. These morbidities may become persistent, affecting patients' prognosis and quality of life in performing activities of daily living.,31,32,34The development of muscular weakness was also associated with CCI and occurred in 60% of our patients, which is consistent with the 30% to 60% rate of occurrence that was reported by other authors. Thus, the findings of the present study contribute to the understanding of CCI, which can lead to the prevention and treatment of functional disabilities and cognitive sequelae resulting from CCI. The characterization of patients with CCI is of fundamental importance for developing proper management plans for a population of individuals who demand large amounts of resources. Combating CCI begins with prevention in the acute phase of the illness and early goal management strategies, including a spectrum of ventilatory, nutritional, and rehabilitation strategies, that are needed when risk factors are detected. In addition, the results presented here can enrich the body of existing knowledge for the development of stratification and prevention tools for critical illness chronification, as well as plans to provide specialized assistance to these patients.,30At the end of one year, CCI mortality occurs in 40% to 50% of patients, and less than 10% recover their physical and/or mental autonomy. The patients' severity according to the SAPS 3 was similar in both groups , which may have contributed to the similarity in mortality, as well as to a selection bias caused by the fatal outcomes of some patients in the Control Group who might have developed CCI. However, contrary to our expectations, hospital mortality was also similar between groups, which was fundamentally conditioned by the deaths that occurred in the ICU; when the deaths among individuals who survived the ICU were evaluated, the odds of death were much higher among the CCI Group than among the Control Group .Intensive care unit mortality was similar between the two groups, which has also been observed by other authors. this factor was not taken into account in our study. Finally, information about care goals for patients in palliative care was not collected, and these patients were not excluded from the analysis.Our study has some limitations. First, it is a study that was carried out in a single hospital with unique characteristics , which does not allow the extrapolation of the results to other hospital institutions. Second, the observation period was only one year. Third, follow-ups of subjects after hospital discharge were not performed, which restricts the extent to which mortality and the quality of life of patients with CCI can be assessed over time in our study. Fourth, although we reported the success of all extubations, the lack of information on the frequency of reintubations is an additional limitation of the study, considering that the muscular weakness that affects the patient with CCI may interfere in the ventilatory weaning process. Fifth, despite blood transfusions independently contribute to an increased risk for hospital deaths, the length of stay, and costs in critically ill patients undergoing prolonged mechanical ventilation,The incidence of chronic critical illness was high and similar to that observed in other studies. Chronification of the critical illness was strongly associated with chronic renal failure being treated by hemodialysis and diagnoses of neurological diseases at hospital admission, and it was related to complications developed during hospitalization, such as pressure ulcers and muscle weakness. Hospital mortality was high and did not differ from that observed in the control population.