The percentage of patients with pain reduction at 7 days after TPI was 88.2% in the immediate effect group and 39.5% in the non-immediate effect group (p < 0.001). The immediate effect of decreased pain had the greatest influence on pain reduction at 7 days, both directly (β = 0.194) and indirectly through increased expectations (β = 0.293), as revealed by path analysis. The effect of a decrease in pain immediately after TPI with local anesthetic affected the subsequent course of MPS pain in patients with incurable cancer by setting expectations as a mediator. There were limitations to the discussion of these findings because this was an observational study.A trigger point injection (TPI) with local anesthetic in myofascial pain syndrome (MPS) often has the immediate effect of a decrease in pain. It is unknown whether the immediate effect of a decrease in pain affects the subsequent course of pain. It is also unknown whether expectations of a decrease in pain mediate such effects. We aimed to clarify how the effect of a decrease in pain immediately after TPI with local anesthetic affected the subsequent course of pain, and whether it increased expectations of a decrease in pain. This was a prospective, single-center, observational clinical trial. Patients with incurable cancer who visited the palliative care department and received TPI with local anesthetic for MPS were prospectively examined. We evaluated whether the immediate effect of a TPI with local anesthetic affects the subsequent course of pain in MPS by setting expectations as a mediator, using path analysis. From 2018 to 2020, 205 patients with incurable cancer received TPI for MPS. Of these, 58.1% of patients reported an immediate effect of decreased pain. Compared with the non-immediate effect group, the immediate effect group had higher expectations of a decrease in pain, and the higher expectation was maintained at 7 days ( The expectations of a decrease in pain have a favorable effect on the subsequent course of pain in patients. A systematic review suggested that positive expectations of a therapy is related to improved health outcomes . One stuTo date, only a few studies have reported the factors that increase patients' expectations of a decrease in pain as a factor in placebo effects. Psychological, neurobiological, and genetic mechanisms have all been reported as factors affecting the placebo effect , 6. FurtIn clinical practice, one of the psychological mechanisms that increase patients' expectations of a decrease in pain is the immediate effect of a decrease in pain (an awareness of a feeling of comfort) immediately after treatment. Our group has previously reported that caregivers caring for family members with cancer are aware of a feeling of comfort immediately after a relaxation therapy session and that the feeling has positive effects on their future quality of life and autonomic nerve function by raising their expectations of the therapy . In the No standard treatment has yet been determined for patients with myofascial pain syndrome (MPS) , but TPIWe therefore hypothesized that the effect of a decrease in pain immediately after TPI would increase the expectations of a decrease in pain in MPS in cancer patients and that it would have a positive effect on the subsequent course of pain as a factor involved in the psychological mechanisms affecting placebo effects.This study was a prospective observational study that evaluated whether the immediate effect of TPI with local anesthetic affected the subsequent course of pain in MPS in patients with incurable cancer by setting expectations as a mediator.The study received approval from the Medical Ethics Committee of Kansai Medical University (reference number: 2018123). Informed consent was not obtained in this study because usual clinical practice was observed, including assessments and treatment. An opt-out method was used so that patients and their families could refuse to participate in the study. The procedures performed in this study were in accordance with the Declaration of Helsinki (as revised in 2013). This study was registered with the University Hospital Medical Information Network Clinical Trials Registry  on July 26, 2020 (retrospectively registered).This study was conducted from 2018 to 2020 at Kansai Medical University Hospital. During this period, patients with incurable cancer who visited the palliative care department were continuously enrolled. Among the enrolled patients, those who received TPI for MPS were included (inclusion criteria). MPS was diagnosed when the following criteria were met: (1) a tender spot was found with palpation, with or without referral of pain; (2) recognition of symptoms by the patient during palpation of the tender spot; and (3) at least three of the following: (a) muscle stiffness or spasm, (b) limited range of motion of an associated joint, (c) pain worsened with stress, and (d) palpation of a taut band and/or nodule associated with a tender spot . A diagnTPI was applied by palliative care physicians to all MPS points observed as pain sites. For the TPI, 1 ml of 1% lidocaine was injected in an unblinded fashion, without ultrasound, to each pain site with a thin needle .Demographic information was obtained from all participants, and included age, sex, outpatients status, primary cancer site, medical treatments, Eastern Cooperative Oncology Group Performance Status (ECOG PS), site of MPS, number of MPS sites, analgesic drug use, and numerical rating scale (NRS) scores for pain and for the expectations of a decrease in pain .The average pain intensity was assessed with an 11-point NRS for pain, ranging from 0 (no pain) to 10 (worst possible pain) . The queThe criterion for an “immediate” effect was determined as ≥33% improvement in the NRS score for pain before and immediately after TPI. The definition of immediate was between 5 and 20 min after TPI. The questionnaire contained the following question: “How intense is your current pain?”The expectation intensity was determined with an NRS assessing expectations of a decrease in pain, ranging from 0 (no pain) to 10 (worst possible pain). The questionnaire was self-administered. The questionnaire contained the following question: “How much do you think your pain will decrease?” The criteria for increased expectations were determined as an NRS score ≥8, or ≥33% improvement in the NRS score assessing expectations of a decrease in pain before and immediately after TPI.The primary outcome was a difference in the rate of patients with pain reduction at 7 days after TPI, between patients with and without a decrease in pain immediately after TPI. The secondary outcomes were changes in the NRS score for pain and in the NRS score assessing expectations of a decrease in pain, correlation and causality between the immediate effect, NRS score reduction at 7 days, increased expectations of a decrease in pain, and adverse events.The estimated number of patients required to detect a minimum rate of patients with a pain reduction difference of 0.15  between the two groups was 186. This value was estimated from published data  , as appropriate. The proportion of participants with an immediate effect of a decrease in pain among all participants and the rate of patients with pain reduction at 7 days after TPI for each group were estimated, including the exact 95% confidence intervals (95% CI).t-tests were used among both groups for the dependent variables: age, number of MPS, NRS score for pain (day 0), and NRS score assessing expectations of a decrease in pain (day 0). Pearson's chi-squared tests were used to analyze the dependent variables: sex, outpatients, medical treatments, ECOG PS, site of MPS, and analgesic drug use.The participants were classified into two groups: an immediate effect group and a non-immediate effect group. Unpaired Changes in the course of NRS scores for pain and NRS scores assessing expectations of a decrease in pain  were analyzed using one-way repeated measures analysis of variance (ANOVA) for each group. To conduct comparisons between groups, the time course was used as the within-participants factor and the group was used as the between-participants factor in two-way repeated measures ANOVA. In the ANOVA, multiple comparisons were corrected using the Bonferroni method. When a participant withdrew from the study, NRS scores after withdrawal were substituted with the score immediately before withdrawal. Changes in analgesic drug administration during the period and loss to follow-up were classified as withdrawal from the study.Spearman's rank correlation coefficients were calculated to assess the associations between NRS reduction at 7 days after TPI and age, ECOG PS, site of MPS (lower back), number of MPS sites, analgesic drug use, NRS score (before TPI), expectations (before TPI), immediate effect of a decrease in pain, increased expectations (immediately and at 7 days after TPI), and NRS score reduction (7 days after TPI).p < 0.05 and adjusting parts with reference to the modification index, and repeating model correction while checking the goodness of fit (GFI) and investigating correlations between factors specifying an NRS score reduction at 7 days. To assess fit, model chi-squared values, GFI, comparative fit index (CFI), root mean square error of approximation (RMSEA), and AIC were used. For a good fit of the model, these measures should be as follows: chi-squared values from 2.0 to 5.0, GIF and CFI values > 0.95, and RMSEA values ≤ 0.08  were mediators of increased expectations immediately after TPI and of an NRS score reduction at 7 days. s ≤ 0.08 . The AICp < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 25.0 and Amos version 25.0 for Macintosh .A value of n = 3) and (2) any comorbidity relating to psychiatric diseases or conditions that made communication difficult (n = 23).During the study period, 1,176 patients with incurable cancer who visited the palliative care department were continuously enrolled. Of the enrolled patients, MPS was observed in 394 patients with incurable cancer, and TPI was recommended in all cases. Of these 394 patients, 231 received TPI to the MPS site and 163 refused TPI for various reasons, including fear of injections. Of these 231 patients, 205 were selected as participants, after excluding 26 patients who met the exclusion criteria: (1) younger than 20 years (n = 119) and the non-immediate effect group (n = 86). Among all participants, 58.1% had an immediate effect of a decrease in pain (95% CI: 51.2–64.9). The participants were classified into the immediate effect group (n = 5) or self-interruption (n = 2) in the non-immediate effect group. No patient lost follow-up during the 7-day follow-up period.Analgesic drug changes during the period were observed in 11 participants (5.4%). Four participants changed their analgesics because of worsened cancer-related pain in the immediate effect group. Seven participants changed their analgesics because of worsened cancer-related pain (p < 0.001) (p < 0.001). Comparing the change rates of NRS scores between groups showed a significant interaction between the time course and group (p < 0.001). There was also a significant difference in time course between the two groups at day 0 (immediately after TPI) and on days 1, 3, and 7 (p < 0.001).The NRS reduction rate at 7 days after TPI was 88.2% (95% CI: 82.4–94.1) in the immediate effect group and 39.5% (95% CI: 29.0–50.1) in the non-immediate effect group (< 0.001) . The chap < 0.001) (p < 0.001). There was also a significant difference in the time course between the groups at day 0 (immediately after TPI) and on days 1, 3, and 7 (p < 0.001).In both groups, the NRS scores assessing expectations of a decrease in pain were significantly higher at all times compared with the baseline (< 0.001) . Comparip = 0.001), the immediate effect of a decrease in pain , increased expectations immediately after TPI , and increased expectations at 7 days after TPI   .R2 values (0.708).The final model demonstrated the data well . The immediate effect of a decrease in pain (immediately after TPI) had the most influence on NRS reduction at 7 days after TPI (β = 0.479) . The immNo adverse events occurred during any of the TPI performed throughout the evaluation period.via a study of MPS in patients with incurable cancer. However, there were limitations to the discussion of these findings because this was an observational study.To the best of our knowledge, this study is the first to report the effect of a decrease in pain immediately after TPI on the subsequent course of pain and on increased expectations of a decrease in pain, The first and most critical finding in the present study was that an immediate effect after TPI with local anesthetic indirectly affected pain reduction at 7 days after TPI, by setting increased expectations of a decrease in pain as a mediator. In the path analysis, the indirect effect (β = 0.285), with increased expectations immediately after TPI as a mediator, was larger than the direct effect (β = 0.194). Being aware of an immediate effect of a decrease in pain (a feeling of comfort) may lead to the expectation that subsequent pain reduction will continue. The immediate effect group had maintained a high NRS score assessing expectations of a decrease in pain by 7 days, so it was possible that longer follow-up effects of 7 days or longer could be expected. The effect of an immediate decrease in pain might have been one factor that increased patients' expectations of a future decrease in pain and may be involved in the psychological mechanisms of placebo analgesia. Fifteen percent of psychotherapy effects have been reported to be a placebo effect, and depend on patients' expectations for treatment . A previvia immediate effects.The immediate effect of TPI with local anesthetic might be caused by its local anesthetic effect. Lidocaine is an aminoamide with an intermediate onset (10–15 min) and an intermediate duration of action (60–120 min), so it often does not have a local anesthetic effect the day after its use . The immThe second important result in this study was that the immediate effect of TPI was associated with pain reduction at 7 days after TPI. The final path model revealed that 70.8% of the NRS score reduction after TPI to MPS sites in patients with incurable cancer could be explained by the immediate effect of a decrease in pain. This result may be useful when introducing treatments for cancer pain; for example, the ability to experience the immediate effects of rapid-release opioids may be tested before starting sustained-release opioids when introducing treatment with opioid analgesics.The effect of a decrease in pain immediately after TPI might be a result of its inactivating effect of the TP. This might be one of the direct effects in path analysis, from the immediate effect to pain reduction at 7 days after TPI. The effect of TP inactivation by TPI might have occurred earlier in the immediate effect group than in the non-immediate effect group, but there are no previous reports on the timing . The shoThe present study has several limitations. First, this study was an observational study, and there were therefore limitations to the discussion of these findings. However, this study provides a basis for future randomized controlled trials. Second, the NRS assessing expectations of a decrease in pain has been used frequently in previous research , 10, butThe effect of a decrease in pain immediately after TPI with local anesthetic affected the subsequent course of pain in MPS in patients with incurable cancer by setting expectations as a mediator.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.The studies involving human participants were reviewed and approved by the ethics committee of Kansai Medical University, Japan (No. 2018123). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.HH, HM, and YM were responsible for the conception and design of this study and data analysis. HH and MF were responsible for data collection and for clinical evaluations. HH wrote the article, which was critically revised by HM, YM, and MF. All authors have approved the final version of this manuscript.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Patients with diabetic polyneuropathy (DPN) may experience paresthesia, dysesthesia, and pain. We aimed to characterize the predictors, symptoms, somatosensory profile, neuropathy severity, and impact of painful DPN and dysesthetic DPN.This study was a cross-sectional study of type 2 diabetes patients with confirmed DPN, diagnosed using widely accepted methods including a clinical examination, skin biopsy, and nerve conduction studies.Of 126 patients with confirmed DPN, 52 had DPN without pain or dysesthesia, 21 had dysesthetic DPN, and 53 painful DPN. Patients with painful DPN were less physically active and suffered from more pain elsewhere than in the feet compared to patients with DPN without pain. Patients with painful DPN had the largest loss of small and large sensory fiber function, and there was a gradient of larger spatial distribution of sensory loss from DPN without dysesthesia/pain to dysesthetic DPN and to painful DPN. This could indicate that patients with dysesthesia had more severe neuropathy than patients without dysesthesia but less than patients with painful DPN. Patients with dysesthetic and painful DPN had higher symptom scores for depression and fatigue than those without dysesthesia/pain with no difference between dysesthetic and painful DPN.There was a gradient of increasing sensory loss from DPN without dysesthesia/pain to dysesthetic DPN and to painful DPN. Pain and dysesthesia are common in DPN and both interfere with daily life. It is therefore important to consider dysesthesia when diagnosing and treating patients with neuropathy. Diabetic polyneuropathy (DPN) is one of the most common complications to type 2 diabetes, affecting up to 50% of the patients . Of thosLittle is known about the risk factors for developing neuropathic pain in those with DPN , 3, 5; hPatients with lesions or disease of the somatosensory nerve system may experience spontaneuous or evoked sensations ranging from paresthesia  over dysesthesia  to pain, which is defined as an unpleasant sensory and emotional experiences associated with, or resembling that associated with, actual or potential tissue damage , 10. TheIn this study, we hypothesized that patients with dysesthesia had more severe neuropathy than patients without dysesthesia but less than patients with neuropathic pain. We also aimed to describe the predictors, symptoms, somatosensory profile and impact of dysesthetic and painful DPN.Patients with DPN participating in a cross-sectional detailed phenotyping study of 389 patients with type 2 diabetes performed from October 2016 to October 2018  were incWe excluded patients with other causes of polyneuropathy and other neurological or pain disorders that could not be distinguished from the symptoms of DPN. We also included 97 controls without diabetes, severe illness or chronic pain of similar age and sex as the patients. They were recruited by flyers and within the social circle of the patient i.e. spouses and friends. The characteristics of the control group without diabetes is described previously . Data frThe patients came in for a 1-day visit that consisted of a structured interview, a clinical examination, and a self-administered questionnaire as described previously . The intThe bedside neurological examination was performed in a quiet environment and consisted of sensory mapping of lower extremities: light brush stroking , pinprick (Owen Mumford Neuropen with sterile neurotips and Semmes-Weinstein monofilament no 5.88 (bending force 75.9 g/745 mN), Stoelting, Wood Dale, IL, USA) and cold (20°C) and warm (40°C) thermal rolls . All modalities were tested in a control area with normal sensation (upper thigh or chest) and then examined starting in the toes and moving proximally. Patients were asked if the stimulus was the same or similar to the control stimulus, less intense, more intense or painful. If it was painful patients rated the pain on the Numeric Rating Scale (NRS). We started the examination systemically on the right side. We also assessed reflexes and muscle strength. To ensure consistency between the 2 investigators, we made a detailed description of the examination, trained together, and tested regularly for agreement.All patients filled in a questionnaire on the day of the clinical examination. The questionnaire consisted of questions about occupational status, educational level, smoking and alcohol consumption , which is the maximum safe amount recommended by the Danish Health Authority). Additionally, the patients reported how often on average per week they were physically active.The patients were asked to rate their overall quality of life (QoL) on the 0–10 NRS, where 10 indicated the best QoL possible and 0 the worst during the last 7 days . We askePatients with dysesthesia and pain filled in the Neuropathic Pain Symptom Inventory (NPSI), a questionnaire designed to evaluate the symptoms of neuropathic pain, their presence, character, and intensity . AlthougWe used a reduced version (9 out of 13 parameters) of the standardized quantitative sensory testing (QST) protocol of the German Research Network for Neuropathic Pain (DFNS) , 28. TheThe NCS included examination of sural nerve bilaterally and the median, peroneal, and tibial nerves unilaterally and we defined polyneuropathy as ≥ 2 nerves with ≥ 1 abnormal parameters with at least 1 sural nerve being abnormal compared with a laboratory control sample –32. IntrSmall fiber neuropathy (SFN), mixed fiber neuropathy (MFN) and large fiber neuropathy (LFN) were defined according to Itani et al. . SFN as Patients were asked if they had constant or recurring pain in the feet, and those with no pain were asked if their abnormal sensory symptoms in the feet were unpleasant (dysesthesia). In patients with no pain or dysesthesia, we did not systematically differentiate between positive and negative sensory symptoms and thus did not record whether the patient had positive sensory symptoms that were not unpleasant (paresthesia). The intensity of pain was scored on an 11-point NRS, 0–10, with 0 indicating no pain and 10 worst pain imaginable. The intensity of dysesthesia/unpleasantness was scored on the NRS with 0 indicating no dysesthesia/unpleasantness and 10 worst dysesthesia/unpleasantness imaginable.Patients with confirmed DPN according to the Toronto consensus criteria were divided into 1. Painful DPN, which included patients with neuropathic pain according to NeuPSIG grading system for neuropathic pain, i.e. patients with pain in both feet, 2. Dysesthetic DPN, which included patients with no pain but with unpleasant abnormal sensations in the feet, and 3. DPN without dysesthesia/pain, which included patients that denied any unpleasant or painful sensations in the feet. Paresthesia was included in this group , 36.All participants signed an informed written consent prior to the examination and the study was approved by the Regional Research Ethics Committee of Central Denmark Region (file number 1-10-72-130-16).For data analysis, we used the STATA version 14  and R Core Team (2019) , 38. DatThe study population consisted of 126 patients with confirmed DPN . Of thosThere were no differences between the three groups of patients in terms of sex, age, BMI, time since diabetes diagnosis, educational level, and occupational status . Fewer pThere was no difference between the groups regarding the proportion of patients with abnormal NCS, whereas almost all patients with dysesthetic or painful DPN had abnormal IENFD values .Patients with dysesthesia and patients with pain had higher scores for depressive symptoms and a higher proportion had abnormal depression scores compared with patients with DPN without dysesthesia/pain. Patients with dysesthesia and pain also had higher fatigue scores than patients without dysesthesia/pain, although there was no difference in the percentages with mild, moderate, or severe interference .P = 0.005).Most patients had experienced dysesthesia or pain for 1–5 years and around 40% for more than 5 years as compared to the median time from diabetes diagnosis of around 6 years. The average intensity of pain was higher than the average intensity of dysesthesia . Pain inThe groups reported a similar frequency and intensity of symptoms on the NPSI, except for stabbing and pins and needles sensations where patients with painful DPN reported higher intensity compared to dyseshthetic DPN .The QST data are summarized in s = 0.35, P <0.001), brush  and warmth (40 C°) . There was also a positive correlation between the number of areas with hyperesthesia and going from no dysesthesia/pain to painful DPN, but in general weak   but a few  had hyperesthesia and 15, 5% had cold and 23, 7% warm hypoesthesia .In this study, we provided a detailed description of patients with dysesthetic and painful DPN in a group of type 2 diabetes patients with relatively newly diagnosed diabetes. Of the 126 patients with confirmed DPN, 51 had no pain or dysesthesia, 21 had dysesthetic DPN, and 53 had painful DPN. We demonstrated that patients with painful DPN had the largest loss of both small and large sensory fiber function in a symmetric, length-dependent distribution and had a larger distribution of sensory abnormalities. There was also a gradient of increasing sensory loss from DPN without dysesthesia/pain to dysesthetic DPN and to painful DPN. The present findings suggest that dysesthesia is present in an intermediate group with less severe neuropathy than those with pain, supporting our hypothesis.Recently conducted studies with similar definitions of DPN and painful DPN found younger age and higher levels of HbA1c , and higIn concert with other studies, we found that patients with painful DPN had more symptoms of depression than patients without pain , 40–42. We found that patients with painful DPN were less physically active compared to patients with DPN without dysesthesia/pain and DPN with dysesthesia. A questionnaire study of patients with longstanding type 1 diabetes found that patients who were more physically active reported less neuropathic pain . This coOnly 30% of the patients with painful DPN used medication normally recommended as a first-line therapy for neuropathic pain , which iWe do not know if dysesthesia presents an intermediate step before development of pain as it is a cross-sectional study and we cannot determine underlying mechanisms from this study. A previous study of patients with neuropathic pain suggested that touch-evoked dysesthesia and pain are transmitted through the same fibers and that the evoked sensation depends on the number of mechanoreceptive fibers that have access to the nociceptive system . PresumaThe main strength of this study is that the study group consisted of patients diagnosed with confirmed DPN according to widely used standards and patients were recruited from a large patient cohort recruited from both general practitioners and diabetes clinics representative of Danish type 2 diabetes patients with relatively short duration of diabetes , 21. TheIn conclusion, there was a gradient in the distribution of sensory loss from DPN without dysesthesia/pain to dysesthesia and then painful DPN, where patients with painful DPN presented with most severe neuropathy. Patients with painful DPN reported less physical activity and patients with pain and dysesthesia had more symptoms of depression than patients with DPN and no pain. The group of patients with dysesthesia resembled patients with pain regarding clinical and demographic data and described their dysesthetic symptoms similar to those with pain according to the NPSI.S1 FigP <0.05 is notified by: *pain vs no dysesthesia/pain, **dysesthesia vs no dysesthesia/pain, ***pain vs dysesthesia.Percentages of patients with loss (-%) and gain (+%) of sensory functions in DPN without dysesthesia/pain, dysesthetic DPN, and painful DPN. WTD, warm detection threshold; CDT, cold detection threshold; TSL, thermal sensory limen; MDT, mechanical detection threshold; VDT, vibration detection threshold; DMA, dynamic mechanical allodynia; PHS, paradoxical heat sensation; MPS, mechanical pain sensitivity; PPT, pressure pain threshold. (TIF)Click here for additional data file.


Background: Chronic lumbar radicular pain often accompanies neuropathic pain. The treatment may follow a screening for probable neuropathic pain rather than the definitive diagnosis, which is often difficult in daily practice. However, interventional management may have limited effects on symptoms in patients with neuropathic radicular pain refractory to conservative treatments. The purpose of this study is to evaluate the factors associated with successful responses after lumbar epidural intervention in patients with chronic lumbar neuropathic radicular pain determined by Douleur Neuropathique 4 (DN4).Methods: We retrospectively reviewed 221 chronic lumbar radicular pain patients using a DN4 questionnaire prior to the epidural interventional procedure. The patients were divided into two groups according to the DN4 questionnaire: <4-point DN4 and ≥4 DN4. The numerical rating scale (NRS) for pain intensity, changes in physical functional status, and the use of pain medication were obtained before and 1 month after the procedure. Successful responder was defined based on robust combination of outcome parameters. The factors associated with successful response were analyzed using univariate and multivariate regression.Results: We found 170 (76.9%) patients with DN4 <4 and 51 (23.1%) with a score ≥4. Among the total 221 patients, 129 (58.4%) were successful responders and 92 (41.6%) were non-responders regardless of DN4 score. We observed a significantly lower proportion of successful responders among patients with a DN4 score ≥4  than patients with a score <4  (P=0.012). After adjusting in multivariate regression analysis, the DN4 score was independently associated with response after lumbar epidural intervention . In subgroup logistic regression analysis according to the DN4 score, adjuvant administration of hypertonic saline during epidural interventions in patients with a DN4 score ≥4  was associated with the success of the lumbar epidural procedure at 1 month.Conclusion: The adjuvant use of hypertonic saline in lumbar epidural interventions may be effective at least 1 month after the intervention in patients with probable neuropathic lumbar radicular pain ≥4 using the DN4. Chronic lower back pain (LBP) or lower leg radicular pain is one of the leading causes of poor quality of life According to the International Association for the Study of Pain, neuropathic pain is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system This retrospective study was conducted at the pain clinic of our institute. The necessity for informed consent was waived as only recorded data were reviewed. We reviewed the electronic medical records of patients for all necessary data that were itemized and recorded at their visits to the pain clinic. This study protocol was approved by our institutional review board , and the study was conducted in accordance with the Declaration of Helsinki.We reviewed the records of patients who first visited our pain clinic from January to December 2016. All aspects of patient privacy and confidentiality were preserved. Patients were included in the present study if they met the following criteria: 1) were at least 20 years of age; 2) had chronic radicular pain and/or lower back pain for more than 3 months; 3) symptoms were not relieved or had not subsided with exercise, medical treatment, or physiotherapy; 4) they used a DN4 questionnaire at the first visit; and 5) they underwent epidural interventional procedure after the first visit. We excluded the patients who had any of the following conditions: 1) age <20 years; 2) acute pain for less than 3 months; 3) signs of progressive neurological deficits or motor weakness; 4) allergies to steroids or contrast dyes; 5) uncontrollable or unstable opioid use; 6) coagulopathy; 7) systemic or injection site infection; 8) unstable medical or psychiatric condition; 9) malignancy; 10) lost to follow-up; and 11) incomplete medical records. Patients were divided according to the DN4 questionnaire: <4-point DN4 group and ≥4-point DN4 group. Patients with a DN4 score ≥4 were considered as having a probable neuropathic pain The lumbar epidural procedures included in this study were lumbar epidural block, caudal epidural block, transforaminal epidural block, percutaneous epidural adhesiolysis with or without a balloon catheter, and pulsed radiofrequency treatment.At the first visit to our institution, we determined the DN4 score of all patients with lumbar radicular pain prior to outpatient treatment. Also, patients were taught to use an 11-point NRS (0 = no pain and 10 = worst possible pain) to assess the intensity of their lumbar radicular pain with or without LBP. The patients were routinely followed up in the outpatient department of our pain clinic 1 month after the lumbar epidural procedures. On follow-up, the NRS pain score and improvement in physical functional status were obtained.The improvement of functional status was judged based on the patient's interview at follow-up visit. It was considered as an improvement in functional status when the patient reported that there was an improvement in daily function at the follow-up visit 1 month after the procedure. In addition, data for pain medication use were collected before and 1 month after the procedure. Based on the World Health Organization (WHO) analgesic ladder, we defined the decrease in the use of pain medication as when the step went down in the WHO analgesic ladder after the procedure compared to before the procedure Data, including age, sex, body mass index, duration of pain, neuropathic component, underlying disease, changing of the medicine, and lumbar magnetic resonance image findings, were collected form electronic medical records.According to previous studies, we defined the responder group with some modifications Continuous demographic data from <4-point DN4 and ≥4 DN4 groups were compared using the Student's t-test. Categorical demographic data were compared using the chi-square test. By using univariate and multivariate regression, the factors associated with successful response 1 month after the epidural intervention were analyzed. The most relevant factors associated with successful responses were included in the univariate logistic regression analysis. The inclusion of variables in the final multivariate logistic regression analysis to evaluate independent factors associated with treatment responses was based on the biological plausibility, clinical importance, and statistical considerations (p <0.2). The quality of fit of the model was assessed with the Hosmer-Lemeshow test. A two-tailed p-value <0.05 was considered statistically significant. The data were analyzed using SPSS software version 21.0 .From January to December 2016, we enrolled 426 patients who visited our pain clinic with a chief complaint of chronic radicular pain and/or lower back pain for more than 3 months and had a DN4 score  patients had DN4 <4 and 51 23.1%) had DN ≥4. The overall baseline demographic characteristics of the 221 patients are shown in Table 3.1% had According to the definition described above, there were 129 (58.4%) responders and 92 (41.6%) non-responders among all patients regardless of DN4 score. However, their demographic and interventional characteristics did not differ  and 2. OTable In addition, we performed subgroup analysis by DN4 scores to investigate factors associated with successful response 1 month after epidural intervention Table . On subgThis study including patients with chronic lumbar radicular pain demonstrated that patients with a DN4 score ≥4 had significantly fewer successful responses 1 month after lumbar epidural interventions than those with a DN4 score <4. However, we found that adjuvant administration of hypertonic saline in lumbar epidural interventions might be associated with the successful response 1 month after the procedures, although these patients had a DN4 score ≥4.Considering the challenge in diagnosing neuropathic pain in daily clinical practice, screening tools for neuropathic pain are important to manage patients with possible neuropathic pain. The DN4 questionnaire is an important screening tool for neuropathic pain, and it has a high sensitivity and specificity in distinguishing neuropathic pain from chronic non-neuropathic pain After screening and identifying probable neuropathic pain, treatment is usually started before the definitive diagnosis of chronic neuropathic radicular pain Hypertonic saline (hyperosmolar sodium chloride) is sometimes used as an adjuvant for epidural interventional procedures There were some limitations in this study. First, this study was retrospective, with restricted data collection. Therefore, a randomized controlled trial should be conducted to evaluate the effect of adjuvant hypertonic saline on lumbar epidural interventions in patients with chronic neuropathic radicular pain. Second, the follow-up period was short. Although patients were evaluated at 1 month in the present study, it would be important to consider the characteristics of neuropathic pain that did not likely respond to the intervention. Third, we included neuroplasty in the lumbar interventional procedure. When performing neuroplasty, hypertonic saline administration is key to the procedure. Therefore, combining neuroplasty with a complex mixture of solutions and mechanical factors may be a bias to the effects of adjuvant hypertonic saline. Finally, the result may vary according to the definition of successful response. Because the criteria of the successful response included the report from the patient interview, subjective factors could influence the success response might lead to different results.In conclusion, the adjuvant use of hypertonic saline in the lumbar epidural intervention may be effective at least 1 month after the intervention in patients with probable neuropathic lumbar radicular pain graded DN4 ≥4.Supplementary tables.Click here for additional data file.


Background: Mild traumatic brain injury (mTBI) often results in post-concussion symptoms, chronic pain, and sleepiness. Genetic factors are thought to play an important role in poor prognosis.Aims: The aims of this study are to (1) document the prevalence of pain and post-concussion symptoms in mTBI patients in acute and chronic phases (2) determine whether candidate genes predispose to post-concussive symptoms and pain.Methods: Posttraumatic symptoms, evaluated using the Rivermead Post-Concussion Symptoms Questionnaire, and pain were assessed in 94 mTBI patients in the acute phase as well as in 22 healthy controls. Assessment was repeated in 36 patients after one year who agreed to participate in the follow-up visit. Gene polymorphisms and expression were assessed in mTBI patients and healthy controls.Results: In the acute phase, mTBI patients with pain (69%) presented more psychological symptoms and sleepiness and were less able to return to work than those without pain. At one year, 19% of mTBI patients had persistent pain and psychological distress. Two haplotypes (H2 and H3) in the brain-derived neurotrophic factor (BDNF) gene were shown to be respectively deleterious and protective against post-concussion symptoms and pain in both acute and chronic phases. Protective haplotype H3 was associated with a decreased expression of the anti-sense of BDNF (BDNF-AS). Deleterious haplotype H2 predicted the development of chronic pain at one year, whereas H3 was protective.Conclusions: This pilot study suggests a protective mechanism of a multilocus effect in BDNF, through BDNF-AS, against post-concussion symptoms and pain in the acute phase and possibly chronic pain at one year post-mTBI. The role of antisense RNA should be validated in larger cohorts. More accurately, it is referred to as a “silent epidemic” because it often leaves patients with post-concussion symptoms such as headaches, mood disturbances, deteriorated quality of life, sleepiness, and chronic pain.3Mild traumatic brain injury (mTBI) refers to a blunt physical trauma to the head that is usually the result of a motor vehicle accident, fall, or sports-related injury. The annual incidence in North America is 100–300/100, 000.4 A systematic review across 12 studies reported headache prevalence at 58% and chronic pain at 51% in civilians  and 43% in veterans.5 We published that mTBI patients with pain had more symptoms of depression and anxiety, higher pain catastrophizing scores, and worse sleep quality with persistent wake-type electroencephalographic activity during sleep than mTBI patients without pain.6 In the TBI sleep literature, sleep–wake disturbances, characterized by excessive daytime sleepiness, fatigue, and pleiosomnia, are the most common complaints from mTBI patients in the days following mTBI.9Post-concussion symptoms commonly co-occur. For instance, 42% of war veterans with traumatic brain injury (TBI) have chronic pain, posttraumatic stress disorder, and post-concussion symptoms.10 The exact mechanisms are still unknown, but it is speculated that hyperarousal mechanisms and central sensitivity might contribute to the co-occurrence of sleep disturbance and pain following injury.11Poor sleep complaints in mTBI patients are comorbid with pain in 20%–25% of cases. More specifically, sleepiness, related fatigue, and diurnal impairment are the most common complaints in this population.15The clinical course and long-term prognosis of mTBI patients differs among individuals. Psychological factors, age, gender, and neurodegenerative factors were previously shown to predispose to the chronicity of symptoms; however, these factors alone do not account for all cases of chronicity.17Another possibility is that mTBI may be a potential catalyst of chronic pain and that the presence of initial post-concussion symptoms  may influence recovery, making it essential to characterize pain contribution as a risk factor.20 Previous studies found that neurocognitive performance following trauma and severity of concussion have been associated with a variety of polymorphisms, with the most commonly identified in apolipoprotein E (ApoE), interleukin-6 (IL-6), catechol-O-methyltransferase (COMT), dopamine receptor D2 DRD2/Ankyrin Repeat and Kinase Domain Containing 1 (ANKK1) Taq1A polymorphism and the brain-derived neurotrophic factor (BDNF), with conflicting results.26 The BDNF gene is located on chromosome 11p14, is 67 kbp long, and spans 12 exons. The expression of BDNF is highly regulated at the level of transcription.27 The Val66Met polymorphism (rs6265), which results in a valine-for-methionine substitution at codon 66, was reported to reduce intracellular trafficking and activity-dependent secretion of BDNF.28 The anti-sense BDNF (BDNF-AS) is known to inhibit BDNF mRNA expression, possibly through RNA duplexes, but changes in the expression of BDNF-AS have not been associated to date with differences in TBI outcomes.29 Neurotrophins, especially BDNF, play an important role in both the modulation of pain-related pathways and synaptic plasticity.31 Its most well-known function is to modulate synaptic efficacy, which results in long-term potentiation, dendritic growth, and synaptic formation and stabilization.33 In a recently published study, BDNF delivered into the brain of mice following experimentally induced TBI improved neurological and cognitive functions, thereby providing a neuroprotective effect.34 BDNF might therefore have an important role in synaptic plasticity of the nociceptive pathway following mTBI through decreased expression of its anti-sense.Genetic predisposition has been proposed to explain part of the variability in individual outcomes following mTBI.Given the large number of mTBI patients seen in emergency departments and the cost for society of managing post-concussion symptoms, it is critical to associate factors and identify early predictors of chronic symptoms in order to facilitate screening for early intervention.The objectives of this study are first to identify the contribution of pain in post-concussion symptoms by comparing mTBI patients with pain to mTBI patients without pain. The second objective is to verify whether known polymorphisms in previously studied genes predispose to general post-concussive symptoms and more specifically to pain following acute mTBI in this cohort and to assess their related gene expression. The third objective is to assess prospectively whether genetic factors predispose for the transition to chronic pain one year post-mTBI. The hypothesis is that functional polymorphisms are important predictors of poor prognosis and chronic pain following mTBI.The study was approved by the ethics committee of the Sacré-Coeur hospital (where subjects were recruited) and the Centre Hospitalier de l’Université de Montréal . All patients gave informed consent before data and blood were collected. In a prospective case–control study design, data were collected from 102 mTBI patients and 22 healthy control subjects with no history of TBI.35: 13–15 on the Glasgow Coma Scale 30 min postinjury; loss of consciousness for 30 min or less; posttraumatic amnesia for less than 24 h; and age 18–65 years. Patients were excluded if they had gross cognitive or speech dysfunction; use of any psychotropic medications or other drugs known to influence pain perception; history of chronic pain or fibromyalgia before mTBI; or presence of major neurological or psychiatric disorders. Eight patients were excluded for the following reasons: not meeting the WHO task force inclusion criteria (n = 2), major depression (n = 3), leukemia (n = 1), chronic alcohol use (n = 1), and collagenosis (n = 1). The final sample included 94 mTBI patients and 22 healthy control subjects.The presence of mTBI was ascertained within 6 weeks of injury and diagnosis was confirmed by a trauma neurosurgeon (JFG) based on the 2004 World Health Organization (WHO) Task Force criteriaAll subjects completed a series of questionnaires and performed the Psychomotor Vigilance Test (PVT) as described below, and all had blood drawn for genotyping. Cell lines were cultured for gene expression analysis from mTBI patients and healthy controls.n = 65; 69%) if they reported pain during the interview and scored higher than “mild pain” on question 7 of the Medical Outcome Study Short-Form 36 (SF-36): “How much bodily pains have you had during the past 4 weeks?” Posttraumatic headache was also assessed, defined as a secondary headache that develops within 7 days after head trauma or after regaining consciousness.36 The other 29 mTBI patients were therefore classified as mTBI without pain.Patients were classified as mTBI patients with pain  agreed. The same experimental paradigm was repeated except for genotyping and cell culture.Medical diagnoses and reports were used to confirm patient eligibility. General physical and emotional health questionnaires, translated in the French language and listed below, were administered at two time points: 6 weeks and one year posttrauma. Data on demographics, education, and return to work were also compiled.Bodily pain intensity was determined on a 100-mm visual analogue scale (VAS).37The Pain Catastrophizing Scale is a validated tool that measures catastrophic pain-related thinking. It assesses the three components of catastrophizing: rumination, magnification, and helplessness, using 13 questions rated on a scale of 0 to 4. Higher scores indicate greater catastrophizing.38The Migraine Disability Assessment (MIDAS) is a seven-item questionnaire. The first five items assess the influence of headaches over the last 3 months. The last two questions assess the total number of days with migraine attacks and the mean pain intensity. The MIDAS score is calculated using the first five questions and the number of days in which migraines interfered with these activities. Disability scores were classified as follows: minimal (0–5), mild (6–10), moderate (11–20), and severe (>21).no problem to 5 = severe problem). The items are headaches, dizziness, nausea, noise and light sensitivity, sleep disturbance, fatigue, irritability, depressive symptoms, frustration, memory, concentration, taking longer to think, blurred and double vision, and restlessness. The overall score is obtained by summing all scores. Higher scores indicate more severe post-concussion symptoms.39Post-concussive symptoms were assessed using the Rivermead Post-Concussion Symptoms Questionnaire in the acute phase posttrauma (<6 weeks). This is the most widely used validated questionnaire for post-concussive symptoms. It contains 16 items that measure the presence and severity of cognitive, emotional, and somatic complaints on a five-point scale . Scores above 26 are classified as severe.44 Subjects were given a handheld computerized device with a red light-emitting diode display of a three-digit millisecond counter and were instructed to press a response button as soon as a visual stimulus appeared on the screen during a 10-min period. Subjects were given pretest training to minimize the practice effect. Mean reaction time (RT) was collected in milliseconds as the primary variable. Higher mean RT represents more sleepiness.Psychomotor vigilance testing  was used to assess sleepiness and reaction time.feeling alert to 7 = no longer fighting sleep.45 Fatigue was assessed by asking: “Please select your current degree of energy.” Possible answers on seven-point Likert-type items ranged from 1 = full energy to 7 = physically exhausted.The Stanford Sleepiness Scale is a one-item question that assesses levels of sleepiness. Its seven-point Likert-type descriptors range from 1 = Genomic DNA was extracted from blood using the Puregene DNA kit  according to the manufacturer’s protocol.54 Using Hap Map Genome Browser release #28 based on data available in August 2010, single nucleotide polymorphisms (SNPs) and tagSNPs were identified and were retained if they had a minor allelic frequency of at least 5% in the EUR (European Ancestry) population. Genotyping of all SNPs was performed using Sequenom IPLEX Gold Technology , according to manufacturer’s instructions, at Génome Québec Innovation Center, Canada.From the literature cited in l-glutamine). RNA was extracted from approximately one million lymphoblastoid cells using the AllPrep DNA/RNA Mini kit  according to the manufacturer’s protocol. The samples were treated with DNase to eliminate genomic DNA contamination. RNA (10 µl) was then reverse transcribed for a total volume of 20 µl containing 10× RT Buffer, 25× dNTP mix (100 mM), 10× Random Primers, Multiscribe Reverse Transcriptase, and RNase inhibitor .Lymphoblastoid cell lines were derived using standard methods from whole blood of mTBI patients and healthy controls and stored in liquid nitrogen until further use. Cells were subsequently thawed and resuspended in 10 ml of B cell media  and peripheral nerve .A database search for statistically significant SNPs in expression quantitative trait loci (eQTL) was done using the publicly available database Genotype–Tissue Expression project.56 In short, the cohort includes samples that were collected postmortem from brain dead subjects following asystole. They consist of snap-frozen DRG sourced from bilateral lumbar L4 and L5. Samples are courtesy of the CORE/CORID repository at the University of Pittsburgh. A total of N = 214 samples with matched genotype/RNA levels were used in this study. The cohort composition was as follows: median age 52, 199/214 Caucasian, 105 females and 109 males.Due to the importance of dorsal root ganglia (DRG) in pain processes, we also looked for the DRG eQTLs data set obtained from the Diatchenko lab (diatchenko.lab.mcgill.ca:/DRG-eQTLs/).Genes whose expression was shown to be modulated by statistically significant SNPs in both databases were tested using quantitative polymerase chain reaction (qPCR).BDNF and BDNF-AS, respectively. Assays were performed in triplicates and results were repeated in a second round and compared to endogenous levels of glyceraldehyde 3-phosphate dehydrogenase (GAPDH).The qPCR reaction was carried out in the ProFlex PCR System (Applied Biosystems) for 10 min at 25°C, 120 min at 37°C, and 5 min at 85°C, followed by cooling to 4°C using cDNA obtained from DNAse-treated RNA samples. Amplifications were performed using TaqMan probe (Hs02718934_s1 and Hs01010223_m1) whose primers map to t test , one-way analysis of variance , or a Mann-Whitney U test when data were not normally distributed and a chi-square test in categorical data cases. A repeated measure ANOVA was used to compare changes across repeated tests  at the two time points.Statistical analyses were performed using SPSS . Data are reported as mean ± SD unless otherwise specified. Group comparisons were performed using a Student’s http://pngu.mgh.harvard.edu/~purcell/PLINK/).57 Single SNP P-values were obtained using association test with the number of minor alleles. A spectral decomposition matrix was applied to account for multiple testing and significance was established at P ≤ 0.00258 An association between SNPs and all available phenotypes was performed.Genetic association analysis was performed using PLINK version 1.07-DOS  was used to construct linkage disequilibrium (LD) blocks with the solid spine method criteria. SNPs within a block where then used for the generation of haplotypes. Haplotype analysis was performed using the expectation–maximization algorithm adapted by Zaykin et al. where haplotype frequencies and associations were generate per individualP = 0.016).Ninety-four mTBI patients  were assessed 46.1 ± 22.6 days posttrauma. Traumatic brain injury was the consequence of a motor vehicle accident for 34 patients (36.1%), a fall for 26 (27.7%), a cycling accident for 19 (20.2%), an assault for 11 (11.7%), and a pedestrian hit by a motor vehicle for four (4.3%). Sixty-five patients (69%) reported pain in the acute posttrauma phase and were classified as mTBI patients with pain. The most common type of pain was accident-related head and neck as well as back pain. Patients with lower Glasgow Coma Scale scores (13 and 14) are protected against pain and an initial Glasgow Coma Scale score of 15 report more pain at 6 weeks  reported occasional pain, namely, back pain (11), neck pain (4), headaches or musculoskeletal pain or shoulder pain (3), knee pain (2), abdominal pain (2), and foot pain (1). In all patients, except for abdominal pain and headaches, the occasional pain was related to work posture or sports. These types of occasional and transient pain were still present at the same intensity in the posttrauma period with the exception of abdominal and muscular pain, which decreased.Posttraumatic headache (PTHA) was assessed with the MIDAS Questionnaire, and 34 (36%) patients reported PTHA, with an average VAS of 60/100 mm lasting for an average of 10 days per month.P < 0.0001. The mTBI with pain group  reported more severe symptoms on the Rivermead Post-Concussion Symptoms Questionnaire , lower quality of life on the SF-36 questionnaire , higher bodily pain scores on the SF-36 , higher overall and component scores on the Pain Catastrophizing Scale , more symptoms of depression on the Beck Depression Inventory , more anxiety symptoms on the Beck Anxiety Inventory (BAI) scores  and more posttraumatic stress symptom scores on the Impact of Event Scale–Revised . Healthy controls presented much lower scores on all administered questionnaires than mTBI patients in general and mTBI patients with pain in particular. However, the difference between controls and mTBI patientswithout pain was not statistically significant for bodily pain SF-36, pain catastrophizing, depression, and anxiety. mTBI patients without pain were significantly more likely to be male  and returned to work faster than mTBI patients with pain .As presented in P ≤ 0.0001), fatigue  and have a longer reaction time on a PVT task than mTBI patients without pain and healthy controls together . There was no statistically significant difference between mTBI patients without pain and controls , whereas two SNPs, including val66met, were protective (rs6265 and rs11030104).All available phenotypes cited above were tested for association with the 31 SNPs. The phenotypes included three main categories: pain-related post-concussion symptoms, psychological and quality of life–related phenotypes, and sleep–wake disturbance–related phenotypes. Full data are presented in Supplemental Table S1. From the entire list of 12 genes, only BDNF gene locus were associated with pain phenotypes but only one SNP with only one phenotype was associated with the DRD2/ANKK1 gene locus, we concentrated on the BDNF gene locus. We first tested whether the effect of SNPs was a mere reflection of functional val/met polymorphism or whether additional functional SNPs exist with the BDNF gene locus. An LD analysis showed that all SNPs in the BDNF gene (except rs908867) span a one-block region of 69 kb  with frequency distributions of more than 1% and chose to retain the top three haplotypes because they account for more than 94.5% of our sample. Conditional haplotype testing was applied to the haplotype composed of rs7124442|rs6265|rs11030104|rs7127507|rs11030121 with the following frequencies: H1: TCTTC (46.8%), H2: CCTCT (27%), and H3: TTCTC (20.7%), where haplotypes H2 and H3 have mirror allelic composition. Results show that H1 is not associated with any phenotype. H2 is associated with more pain and more post-concussive symptoms and hence has a deleterious effect, and H3 is associated with less pain, better quality of life, and less fatigue and sleepiness and hence is protective . The dirBDNF and its antisense BDNF-AS. We found none of the eQTLs in the blood; however, rs11030121, rs7124442, and rs7127507, which are markers of haplotype H2, are associated with a decreased expression of BDNF-AS as well as an increase in the expression of BDNF in the DRG. On the other hand, markers of haplotypes H3, rs6265, and rs11030104 are associated with decreased BDNF-AS in the cortex and nerves as well as a decrease in BDNF in nerves  agreed to participate in the one-year follow-up (mean = 429.9 ± 59.4 days posttrauma). After one year, ten remained pain free, eight had no more pain, three had developed new onset pain (head and neck pain), and 15 still had (persistent) pain. Overall, 18 out of the 36 of mTBI patients reported chronic pain, with a mean pain VAS score of 36.2/100 mm (SD ± 19.5), compared to mTBI patients without pain, mean VAS score of 6.3/100 (SD ± 15.4); n = 18) reported more severe symptoms on the Rivermead Post-Concussion Symptoms Questionnaire compared to mTBI patients without chronic pain , lower quality of life on the SF-36 questionnaire , more bodily pain on the SF-36 , higher depression scores on the BDI , and higher anxiety scores on the BAI . The Pain Catastrophizing Scale score and the Impact of Event Scale showed no statistical difference between the two groups at follow-up, even if they were higher in the pain group. No differences were found on sleepiness, fatigue, and mean reaction time on the PVT for both groups , whereas carriers of haplotype H3 are protected against development of chronic pain . The frequencies of H1, H2, and H3 respectively differed in mTBI with persistent or newly developed pain versus mTBI with no pain . Due to the low sample size (n = 18 per group), these results are preliminary.mTBI patients with chronic pain were more likely to carry haplotype H2 , which is known to inhibit BDNF mRNA expression, possibly through RNA duplexes.29 We could then speculate that the H3 haplotype, which includes the met allele, is protective because it disinhibits BDNF expression and favors BDNF release. In lymphoblastoid cell lines, however, we were not able to demonstrate an increase in BDNF, due to the low expression of BDNF in these cells as well as the low sample size. When our results are compared to public eQTL databases, the same pattern of expression is observed. Therefore, genetic susceptibility in factors regulating brain plasticity may play an important role in neuronal recovery following mTBI. In this article, we introduce the concept that there is a multilocus effect of BDNF haplotypes affecting post-concussion symptoms. This effect may be driven by the antisense, leading to beneficial BDNF presence.In the present study, we show that haplotype H3, which has methionine as a marker, decreases the expression of anti-sense BDNF  developed pain that was absent in the acute posttrauma phase. A possible explanation is that pain in the acute phase was well controlled and therefore not reflected in the questionnaires or medical reports.BDNF for chronic post-mTBI pain; however, due to low sample size, these are only preliminary findings.The most significant finding is that haplotype H2 is a predictor of persistent or newly developed chronic pain in mTBI patients and carriers of haplotype H3 are protected from the development of chronicity. To our knowledge, this is the first study to demonstrate the role of multiple loci in 66 because this low recruitment rate can introduce a bias in the results and weaken the development of knowledge within the field. Second, we used psychomotor vigilance testing to assess mean reaction time. Although it has been validated in sleep deprivation studies, we were unable to find a validation study in a cohort of mTBI patients, which limited our ability to reference its use in this population. Third, BDNF expression was measured in lymphoblastoid cell line because they were the only resources available to us. Though endogenous expression of BDNF was confirmed in these cells, neuronal or glial cell lines would have been more appropriate.67 Last, the sample size of this study is too small to draw definitive conclusions on the association between BDNF and pain related outcomes in TBI; however, the results presented should be taken into consideration for future trials with larger cohorts.Our study has certain limitations that need to be addressed. First, despite considerable efforts, the one-year follow-up rate of recruited patients was relatively low at 38%. The difficulties in recruitment in TBI studies are a subject addressed in a growing body of literature with proposed solutions to be implemented in the future,BDNF-AS is key for the protective effect of BDNF haplotypes through a multilocus effect against post-concussion symptoms and pain in the acute phase and, most important, for the development of chronic pain following mTBI. Future studies should focus on mechanisms of inhibition of BDNF-AS as a potential therapeutic target. Increasing evidence thus points to an immediate BDNF response in the central nervous system following trauma. The identification of at-risk patients as well as the consequences of better control of post-concussion symptoms in the acute posttrauma phase should be considered when assessing mTBI.This study shows that Click here for additional data file.


Temporomandibular disorders have a considerable prevalence, with a significant impact on physical and psychosocial factors . It contA case study of a 25-year-old female patient with generalised headache, generalised myofascial pain (III) in the head and neck region, self-reported awake and sleep bruxism and important psychological factors related to catastrophic pain and anxiety, all described during the initial interview. The patient can positively correlate beginning of the manifestation of the painful symptoms with relevant psychosocial and drastic, in her own words, family changes. Pain intensity and headache are measured with numeric pain rating scale (NPRS) and the patient is submitted to one session of physical therapy per week. The treatment plan consisted of cognitive-behavioral therapy with a first appointment based on education, habits recognition and modification, the patient was medicated with muscle relaxants and off label gabapentine, physiotherapy and psychotherapy. All the assumptions of the Helsinki Declaration have been fulfilled and an informed consent for clinical case of Clinica Dentária Egas Moniz approved by the ethic commission of Instituto Universitário Egas Moniz.Three months after  the beginning of the treatment plan, the biggest breakthrough was the ability of the patient to identify psychological situations that trigger the exacerbation of pain. The patient referred absence of headache, a significant reduction of myofascial pain (I) located in the masseter and in the temporal of about 70% of the pain scale and changed from myofascial pain to local myalgia.Psychosocial factors are frequently present in patients with temporomandibular disorders and their evaluation, grading and consequent intervention become important for the prognosis and resolution of the case.The assessment of psychosocial aspects should be considered in all patients with temporomandibular disorders in order to analyse, case by case, whether they are relevant for controlling their symptoms. It will be important to carry out a experimental study with a larger sample to verify whether the obtained results point in the same direction.


A high CCI score was associated with increased 30-day mortality in patients with MINS, suggesting that the CCI may need to be considered when predicting outcomes of MINS patients.Myocardial injury after non-cardiac surgery (MINS) is a well-known and relevant indicator of early postoperative mortality, but factors related to increased mortality in MINS patients are as yet unknown. The Charlson Comorbidity Index (CCI) is widely used to classify various comorbid conditions and underlying diseases. Our study aimed to determine the prognostic value of CCI with regard to mortality of patients with MINS. This study comprises 5633 patients who had MINS as diagnosed by a rise of postoperative cardiac troponin I above the normal range (≥ 0.04 ng/mL) from January 2010 to June 2019. Patients were divided into two groups according to median weighted CCI score: low CCI (≤ 2) and high CCI (> 2) groups. The primary outcome was 30-day mortality after surgery, and secondary outcomes were 1-year and overall mortalities. Of the 5633 patients, 3428 (60.9%) were in the low CCI group (1.21 ± 0.84) and 2205 (39.1%) were in the high CCI group (4.17 ± 1.82). After propensity score matching, mortality during the first 30 days after surgery was significantly greater in the high CCI group than the low CCI group (9.4% vs. 6.0%, respectively; hazard ratio 1.56, 95% confidence interval 1.23–1.98,  The Charlson Comorbidity Index (CCI) was introduced in 1987 to classify the severity of comorbid conditions5. Since then, it has been validated as a reliable tool for predicting prognosis and has been updated with different weights for various diseases7. Recent CCI scoring systems with updated weights have been reported to correlate well with the prognoses of critically ill patients and those undergoing surgical procedures8. The CCI is one of the most widely used stratification tools familiar to clinicians in different medical fields and is credited highly for its validation in an extensive database, especially when mortality is the outcome of interest9.The presence of comorbid conditions is associated with reduced survival of patients in various clinical situations10. MINS is diagnosed in the presence of postoperative cardiac troponin (cTn) elevation related to ischemia within 30 days after non-cardiac surgery, with or without ischemic symptoms11. The incidence of MINS for all non-cardiac surgeries has been estimated to be as high as 17.9%, and comorbidities such as hypertension, coronary artery disease, heart failure, prior myocardial infarction, and kidney disease significantly increase the risk of MINS12. However, it is unclear whether the effects of comorbidities extend to the short-term mortality of patients after MINS diagnosis. Therefore, in this study, we used the CCI to grade the severity of comorbidities in MINS patients and evaluated the incidence of postoperative 30-day mortality.Myocardial injury after non-cardiac surgery (MINS) is associated with adverse postoperative outcomes including death, non-fatal cardiac arrest, dysfunction, congestive heart failure, and strokeA total of 43,019 patients undergoing non-cardiac surgery between January 2010 and June 2019, were identified in the registry. Among these patients, we excluded (1) 1154 patients younger than 18 years at the time of surgery (2) 35,990 patients with no postoperative cTn measurement or elevation and (3) 242 patients with cTn elevation due to non-ischemic etiology.The final study cohort consisted of 5633 patients diagnosed with MINS. These patients were then stratified into two groups according to median weighted CCI value: 3428 (60.9%) patients were allocated to the low CCI group and 2205 39.1%) patients to the high CCI group. A flowchart of the present study is presented in Fig. % patientp < 0.001 for univariable analysis and HR 1.72, 95% CI 1.39–2.13, p < 0.001 for multivariable analysis) (Table p < 0.001). Mortalities during the one-year and overall follow-up periods were higher in the high CCI group than the low CCI group   (Table p = 0.48) but was related to mortality during one year or the overall follow-up period , and the high CCI group had a significantly higher risk of 30-day mortality compared to the low CCI group before and after multivariable adjustment  1.58, 95% confidence interval (CI) 1.30–1.92, p for interaction = 0.04), and 30-day mortality of MINS was significantly increased by high CCI only in patients without hypertension   Fig. . In the In this observational study, MINS patients with a higher CCI score showed a significant increase in mortality during the first 30 days after surgery compared to those with a lower CCI score. In addition, one-year mortality and overall mortality were also significantly higher in the high CCI group. Our finding suggests that CCI may help identify MINS patients who are at higher mortality risk.13. The original version featured 17 conditions and assigned weights for each condition based on the adjusted relative risk of one-year mortality5. This comorbidity index has been verified to assess mortality and prognosis14. Owing to the advances in medical treatment and disease management, weights were reassigned to 12 variables based on ICD-10 code in the updated version in 20119. Five variables, including myocardial infarction, were reassigned to a weight of 0  code or an individual’s electronic medical records9. It is defined as a myocardial injury caused by ischemia, with at least one value of cardiac troponin elevation above the 99th percentile upper reference limit, without the requirement of ischemic symptoms16. Myocardial ischemia can be caused by pre-existing coronary disease or thrombosis or myocardial oxygen supply and demand mismatch17. Considering the etiology of MINS, antithrombotic agents  and anticoagulants  can be used for treatment. Aspirin and statin therapies and early cardiology assessment and intervention of patients decrease 30-day mortality of MINS patients18.MINS is an independent predictor of 30-day mortality and the most common perioperative cardiovascular complication19. Patients with comorbidities are vulnerable to MINS despite diagnostic criteria that exclude cTn elevation with a definite non-ischemic cause12. This study delineates the impact of comorbidities on the increased 30-day mortality in MINS patients as not only a consequence of acute coronary ischemic changes, but also accounting for the poor general conditions and metabolic burdens, graded by the CCI scoring system. Our results also indicate that comorbidities stratified by the CCI are associated with mortality after diagnosis of MINS, and that this association is valid even in the short-term follow-up period. Moreover, the conclusion was supported by a conflicting result in patients without MINS, in whom the CCI score was not an independent predictor of 30-day mortality. The detrimental effects of comorbidities included in the CCI were significant only in patients diagnosed with MINS.Although cTn is a sensitive and specific biomarker of cardiac myocyte damage, ischemic injury is not the only cause of cTn elevation. A broad spectrum of diseases, including non-coronary and even non-cardiac conditions, is associated with cTn elevationWe further stratified the patients into four groups according to quartile of CCI. The results showed that, compared with the 1st quartile group, 30-day mortality was significantly higher in the 3rd and 4th quartile groups, with no significant difference between the 1st and 2nd quartile groups. This implies that MINS mortality is affected by comorbidities only when they exceed a certain severity. Therefore, we estimated the threshold associated with 30-day mortality, which was a CCI of 2. However, the area under the curve was relatively low, as were the sensitivity and specificity. In addition, subgroup analysis revealed an association between high CCI and MINS mortality only in patients without a history of hypertension. Hypertension is not one of the 12 components of CCI, and the result of subgroup analysis implies that hypertension can affect the association between mortality due to MINS and other CCI components. This suggests that comorbidities not included in the CCI should also be considered for the incidence of 30-day mortality in MINS patients. Due to the conflicting results from the subgroup analysis and the limitation of the low ROC, the CCI cannot be relied upon solely when assessing mortality in patients with MINS. However, our study shows that patients with higher CCI have a significantly higher risk of mortality than those with lower CCI, emphasizing the need for patient surveillance and intensive treatment for MINS patients with high CCI.This study had several limitations. First, due to the nature of a retrospective, observational study, the results might have been influenced by undiscovered confounding factors, despite the use of statistical adjustment including propensity matching and multivariable analysis. Second, the analysis included only patients with available cTn measurements, which were performed selectively. Our results from selected patients with known risk might not be generalizable to all patients. Last, detailed preoperative cardiac evaluations other than cTn level, such as left ventricular ejection fraction or coronary artery angiograms, were unavailable for all patients. Our results may not be sufficient to recommend a routine adaptation of CCI to fully predict mortality of MINS patients, but still suggest that upon using the CCI, the severity of the individual’s comorbidity and associated risks can be estimated. Higher CCI may encourage clinicians to intervene earlier than lower CCI, in order to avoid further adverse events including death.20.This study is a retrospective chart review and was approved by the Institutional Review Board of Samsung Medical Center (SMC 2019-08-048). The need for written informed consent for access to the registry was waived by the Institutional Review Board of Samsung Medical Center as the entire dataset was extracted in de-identified form. The present study was conducted in reference to the precepts of the Declaration of Helsinki, and results are reported according to “Strengthening the Reporting of Observational Studies in Epidemiology”All pre-, intra-, and postoperative data were obtained from the SMC-TINCO registry , which contains the data of 43,019 consecutive patients with at least one cTn I measurement during a preoperative evaluation or within 30 postoperative days of non-cardiac surgery between January 2010 and June 2019, at Samsung Medical Center, Seoul, South Korea. Data were generated using “Clinical Data Warehouse Darwin-C,” an institutional electronic medical archive system for retrieval of de-identified medical and administrative records. Mortality statistics were derived from our institution’s medical records; mortalities in other institutions were verified with the National Population Registry of the Korea National Statistical Office.21. Following current diagnostic criteria, cTn elevation with evidence of a non-ischemic etiology such as pulmonary embolism, atrial fibrillation, cardioversion, sepsis, or chronic cTn elevation was not considered MINS15. The comorbidity of each patient was quantified using Quan et al.’s updated version of CCI, which is comprised of a summation score of 12 medical conditions with varying weights assigned based on chart review or derived from administrative data with ICD-10 codes8. A score of 1 was given for chronic pulmonary disease, diabetes with chronic complications, rheumatologic disease, and renal disease; a score of 2 was assigned to congestive heart failure, dementia, mild liver disease, hemi or paraplegia, any malignancy including leukemia and lymphoma; a score of 4 was used for moderate to severe liver disease and acquired immunodeficiency syndrome; and a score of 6 was assigned to a metastatic solid tumor8. The sum of all comorbidities yields a single comorbidity score for a patient, with a value of 0 indicating no comorbidity and higher values indicating more severe comorbidity8. High-risk surgery was classified as that with a reported risk of mortality greater than 5% according to the 2014 European Society of Cardiology/European Society of Anesthesiology (ESC/ESA) guidelines22.For this study, we identified patients who were diagnosed with MINS and allocated them into two groups according to median CCI value: patients with CCI ≤ 2 (low group) and those with CCI > 2 (high group). MINS was defined as an elevation of cTn I level as measured by an automated analyzer  above the 99th percentile of the upper reference limit within 30 postoperative days. The lowest measurable value was 6 ng/L, and the 99th percentile cutoff for cTn I was 40 ng/LThe primary outcome was all-cause mortality during 30 postoperative days, and the mortalities during one year and overall follow-up were compared as secondary outcomes.Perioperative management including anesthetic practice and perioperative care follow institutional protocols, which are based on current guidelines. In our hospital, perioperative cTn I measurements were not performed routinely in non-cardiac surgery but were performed selectively at the recommendation of the cardiologist or for patients with one or more major cardiovascular risk factors, such as a history of heart failure, ischemic heart disease, stroke, transient ischemic attack, diabetes mellitus on insulin therapy, or chs3 ronic kidney disease, or for those undergoing high-risk surgery. When cTn elevation was detected, patients were referred to cardiologists for further workup  or received secondary preventive drugs.p-value < 0.05 were retained in the multivariable Cox regression model, comprising sex, operation duration, alcohol consumption, high-risk operation, general anesthesia, emergency surgery, preoperative use of a beta-blocker, intraoperative use of continuous inotropics, and red blood cell transfusion. To reduce selection bias and the effects of potential confounding factors, a 1:1 propensity score matched analysis without replacement was conducted. Absolute standardized mean differences (ASD) lower than 10% were regarded as well-balanced variables between groups. Kaplan–Meier estimates were conducted for survival analysis, and these were compared with the log-rank test. Subgroup analysis was conducted to reveal any interactions of male sex, coronary artery disease, hypertension, emergency operation, high-risk operation, and active cancer with relevant factors and is presented as a forest plot. To evaluate the capability of CCI to predict 30-day mortality, Pearson’s correlation coefficient was estimated. A ROC plot was constructed to calculate the threshold CCI score and to compute its specificity and sensitivity as a predictive factor. The potential impact of unmeasured confounders was estimated in the sensitivity analysis. This analysis estimates the effect of an unmeasured binary confounder on the measured causal association between a binary exposure and a binary outcome assuming that the prevalence of the unmeasured confounder is 40%23. The power of this study for the given sample size was evaluated using Spearman's rank correlation24 and was 0.91 and 0.98 for estimated HRs of 1.4 and 1.5, respectively. All statistical analyses were performed with R 4.0.2  using the PowerSurvEpi package. All reported p-value were two-tailed, and statistical significance was assumed at p-value < 0.05.Baseline characteristics are presented as means ± standard deviations (SD) or medians with interquartile ranges (IQRs) for continuous variables and as numbers (%) for categorical variables. For continuous data, differences were compared by t-test or Mann–Whitney test, and categorical data were compared using the chi-square or Fisher’s exact test. Mortalities were compared using Cox regression analysis; results are reported as HRs and 95% confidence intervals CIs. Clinically relevant variables and those with a Supplementary Information.


We conducted a time-to-event analysis censored at 28 days. Specifically, we determined the relationship between metabolites and time to extubation and freedom from vasopressors using a competing risk survival model, with death as a competing risk. We also compared metabolite concentrations between CCI patients, defined as intensive care unit level of care ≥ 14 days, and those with rapid recovery. Elevations in two acylcarnitines and four amino acids were related to the freedom from organ support . Proline, glycine, glutamine, and methionine were also elevated in patients who developed CCI. Our work highlights the need for further testing of metabolomics to identify patients at risk of CCI and to elucidate potential mechanisms that contribute to its etiology.Sepsis-induced metabolic dysfunction is associated with mortality, but the signatures that differentiate variable clinical outcomes among survivors are unknown. Our aim was to determine the relationship between host metabolism and chronic critical illness (CCI) in patients with septic shock. We analyzed metabolomics data from mechanically ventilated patients with vasopressor-dependent septic shock from the placebo arm of a recently completed clinical trial. Baseline serum metabolites were measured by liquid chromatography-mass spectrometry and  Sepsis is a prevalent, costly, and life-threatening syndrome, formally defined as organ dysfunction occurring secondary to an infection resulting from a dysregulated host response ,2,3. MorPrevious attempts to discriminate who is at risk for developing CCI using electronic health record data at ICU admission have proven unsuccessful ,11,12. TSepsis induces a deranged energy metabolism that manifests as elevated blood lactate and glucose levels, muscle catabolism and perturbed amino acid concentrations, and mitochondrial dysfunction ,18,19. MThe Effect of Levocarnitine vs. Placebo as an Adjunctive Treatment for Septic Shock —the Rapid Administration of Carnitine in Sepsis (RACE) clinical trial was a multicenter, placebo-controlled, phase II study that adaptively randomized patients with vasopressor-dependent septic shock and moderate organ dysfunction to saline placebo or low (6 g), medium (12 g), or high dose (18 g) levocarnitine . Enrolleclinicaltrials.gov  and approved by the Institutional Review Board of all participating study sites. The trial was conducted ethically according to Good Clinical Practice guidelines and in accordance with local and federal guidelines and statutes.All patients or their legally authorized representative provided informed consent and the trial protocol was registered with Detailed descriptions of the blood sampling, handling, and processing from this cohort have been previously reported ,30. BrieAcylcarnitines were measured by reverse-phase liquid chromatography mass spectrometry (LC-MS/MS) at the Michigan Regional Comprehensive Metabolomics Research Core as previously described . Samples1H-NMR) on a Varian  11.74 Tesla (500 MHz) spectrometer consistent with our prior methods [Abundant polar compounds were measured by quantitative proton nuclear magnetic resonance  procedure of Benjamini–Hochberg [For the primary outcome, we considered each patient’s ventilator-free days and vasopressor-free days as a time-to-event analysis censored at 28 days, with death as a competing risk ,37. SpecHochberg . MetabolTo help further visualize the results of the competing risk models, we dichotomized the cohort based on the median value of the top metabolic predictor. We then plotted time to event curves for successful extubation and freedom from vasopressors over 28 days in patients at or above and those below the median metabolite concentration. Patients who died during the 28 days were considered to have zero ventilator-free days and vasopressor-free days to account for the competing risk of death .p-values were corrected for multiple comparison as described above, and post-hoc testing for between-group differences was performed for metabolites with an FDR < 0.05 according to Fisher’s Least Square Difference. All data analysis and figure generation were completed in Metaboanalyst  or RStudio with R  [As an exploratory analysis, we sought to determine the relationship between host metabolism and CCI. Importantly, enrollment and blood sampling in the RACE clinical trial were anchored to onset of septic shock rather than ICU admission. While total patient days in the ICU were recorded, it was not possible to determine how long a patient had been in the ICU prior to enrollment in the study. This complicated our ability to classify patients into common phenotypes of CCI that are derived from ICU length of stay ,43,44,45MA, USA) ,47.N = 21/47; 44.7%) were successfully extubated and free of vasopressors over 28 days, 6  required persistent mechanical ventilation and/or vasopressors, and 20  died prior to 28 days. Patient characteristics at baseline are provided in the supplement  and 27 small, polar molecules by NMR (N = 46). Levocarnitine (LC) and acetylcarnitine (C2) are measured by both methods. A comprehensive list of these metabolites is available in the https://www.metabolomicsworkbench.org/; accession number ST001319, accessed on 1 December 2021).We identified and measured twenty-four acylcarnitine species by LC-MS/MS , 17  experienced a rapid recovery, and 20  died prior to 28 days. Patients who experienced a rapid recovery were more likely to be alive at one year compared to patients who developed CCI . In multivariable PCA analysis, metabolic differences were most pronounced in the mortality outcome group. There was substantial overlap between patients who developed CCI and those who experienced rapid recovery  and four amino acids  are related to liberation from mechanical ventilation and vasopressors over 28 days. Additionally, we found that these same amino acids were elevated in CCI patients who required at least 14 days of mechanical ventilation and/or vasopressors relative to those who rapidly recovered. Our findings provide new insights into candidate biochemical pathways that are perturbed in sepsis survivors and suggest metabolomics may provide prognostic detail beyond mortality outcomes.A dysregulated host metabolic response is formally defined in the Sepsis-3 definition and is being increasingly understood as a hallmark of sepsis pathophysiology ,49. ThisOther proposed metabolic biomarkers of CCI have included low serum albumin and increased frailty  , and theDifferentiating blood levels of amino acids are metrics of the overall energy economy of the host and are related to patient outcomes in critical illnesses ,62. We hOur study has important limitations that warrant further consideration. First, our study was cross-sectional in nature, leveraging only a single metabolic timepoint. While the collection of serum samples was carefully anchored to a clinical event , future work that follows the trajectory of metabolic changes in the ICU may provide additional prognostic value and mechanistic insight. In addition, we considered only a limited read of the serum metabolome using normalized concentrations and acknowledge that our metabolomics data are not comprehensive. Absolute quantification of potential biomarkers will be essential for ultimate clinical translation, while a broader read of the metabolome combined with data acquired at the transcription and protein level offers an exciting and potentially more fruitful assessment of the pathophysiology of CCI. Moreover, we used a definition of CCI based on the continuous need for mechanical ventilation and vasopressors, while much of the CCI literature relies on ICU length of stay. Finally, our study was observational and thus our findings are hypothesis-generating and require rigorous validation in prospective cohorts.Among mechanically ventilated patients with septic shock, serum concentrations of two acylcarnitines and four amino acids were related to the time to extubation and freedom from vasopressors. Our work supports the feasibility of metabolomics to interrogate the mechanisms of CCI and the hypothesis that altered host metabolism is a sign of and/or contributes to CCI.