Fibromyalgia syndrome (FMS) is a chronic rheumatologic disease characterized by widespread musculoskeletal pain and other psychopathological symptoms which have a negative impact on patients’ quality of life. FMS is frequently associated with alexithymia, a multidimensional construct characterized by difficulty in identifying feelings (DIF) and verbally communicating them difficulty describing feelings (DDF) and an externally oriented cognitive thinking style (EOT). The aim of the present study was to investigate the relationship between alexithymia, anxious and depressive symptoms and pain perception, in patients with FMS and other rheumatic diseases (RD).The sample consisted of 127 participants , of which 48 with FMS, 41 with RD and 38 healthy control group (HC). All groups underwent to a test battery investigating anxiety and depressive symptoms (HADS), pain  and alexithymia (TAS-20).n = 89), alexithymic patients  exhibited higher scores in pain and psychological distress compared to non-alexithymic patients . Regression analysis found no relationship between alexithymia and pain in AL, meanwhile pain intensity was predicted by anxiety in N-AL.A high prevalence of alexithymia (TAS ≥ 61) was found in FMS (47.9%) and RD (41.5%) patients, compared to the HC group (2.6%). FMS patients showed significant higher scores than HC on DIF, DDF, EOT, anxiety and depression. The clinical sample, FMS and RD groups combined  in patients with fibromyalgia or rheumatic diseases, correlations were found on the one side, between alexithymia and psychological distress, on the other side, between pain experience and intensity. Meanwhile, when symptoms of psychological distress and alexithymia were subthreshold, correlations with pain experience and intensity became stronger. Fibromyalgia syndrome (FMS) is a chronic condition characterized by widespread musculoskeletal pain, tenderness of the muscles, stiffness and extra-articular symptoms such as fatigue, anxiety, sleep disorders depression and functional impairment of daily living activities . These fIn the context of fibromyalgia, several studies have shown that fibromyalgia is a widespread condition, commonly occurring in young or middle-aged females and the prevalence in the general population is between 0.5 and 5% .Despite the increasing knowledge about FMS, the etiopathogenesis of the disease is still unclear. Many factors seem to be involved: genetic, immunological, hormonal, psychological and environmental . CentralChronic and diffuse pain seems to be the core symptom of FMS, is associated with a high sensitivity to touch, a lowering of pain threshold, headache, gastrointestinal disorders and severe fatigue . Sleep dAdditionally, FMS in females seems to be associated with sexual dysfunctions, such as decreased sexual desire and the presence of pain during sexual intercourse, though psychiatric comorbidity may have more influence on sexual satisfaction than the presence of the rheumatic disease itself .Psychiatric disorders such as depression, anxiety, obsessive-compulsive disorder and post-traumatic stress disorder are frequently comorbid with FMS . The mosChronic pain conditions seem to be associated with the presence of alexithymic traits, in particular disorders such as chronic low back pain, FMS, temporomandibular pain and myofascial pain syndrome . Some stThe theoretical stance that alexithymia is a personological trait characterized by a deficit of regulation and emotional processing, has made this construct particularly useful in exploring the role of personality and emotions in the pathogenesis of different somatic diseases . AssociaOverall the presence of alexithymia in patients with chronic pain and its influence on pain intensity is still unclear: many studies haven’t found significant associations , while oSeveral studies have pointed out that differences in levels of alexithymia of FMS and healthy controls significantly decrease or disappear once anxiety and depression are statistically controlled, supporting the view that alexithymia may represent a state phenomenon that varies in relation to severity of clinical symptoms . MontoroTherefore, the precise role of alexithymia in fibromyalgia has not yet been clarified. The present work aims to investigate and clarify the relationship between alexithymia, pain, anxiety and depression in FMS patients. The first aim is to further evaluate alexithymia in FMS patients, in comparison with healthy subjects and patients with other chronic pain pathologies, such as arthritis, and to explore its relationship with pain perception and other psychological factors, such as emotional distress (anxiety and depression). The second aim is to verify whether alexithymia is related to pain perception (in its sensory and affective components) and pain intensity, and to what extent psychological distress, especially anxiety and depression, is involved in this relationship.According to previous researches, we hypothesized that FMS and RD patients would exhibit higher levels of alexithymia, pain perception, anxiety and depression while compared with HC. We also hypothesized that alexithymia might influence pain affective dimension, as it might be a state phenomenon that varies in relation to severity of anxious and depressive symptoms.n = 48), according the ACR criteria (n = 41). All patients had a main diagnosis, made by an expert rheumatologist. The exclusion criteria for both groups were: age below 18, education level below 5 years, insufficient knowledge of Italian language and presence of an important neurological and/or psychiatric disorder.One hundred and twenty-seven subjects with a mean age of 51.97 years (SD = 11.14) were recruited for the study. Chronic pain patients were recruited between May and December 2018 at the University of Pisa Hospital’s Rheumatology Unit (A.O.U.P). The clinical sample consisted of two groups: patients with a diagnosis of either FMS  was recruited from patients’ partners or relatives that accompanied them to visit. They had no history of chronic pain and met the same exclusion criteria.The healthy control group   .r = 0.94, p < 0.001)  .r = 0.70)  .To assess symptoms of psychological distress, the Italian adaptation of the Hospital Anxiety and Depression Scale was used HADS; . This int-test for independent samples was used to assess differences between subgroups. Pearson’s coefficient was computed to evaluate variables correlations and multivariate linear regression was performed. P values <0.05 were considered statistically significant. The analysis was conducted using IBM SPSS statistics version 25.Distributions were assessed using the Kolmogorov–Smirnov test. All clinical variables for FMS, RD and HC groups were not normally distributed, and so the data were analyzed using Kruskal-Wallis with Dunn’s multiple comparisons. Spearman’s correlation was computed to evaluate the relationship between alexithymia, pain perception and intensity, anxiety and depression. Partial correlations were performed to control anxiety and depression effects. All clinical variables were normally distributed in the Alexithymia and No Alexithymia subgroups: A sample of 48 patients with FMS diagnosis , 41 patients with rheumatic disease diagnosis  and a control group of 38 healthy subjects  were included in the present study. Demographic characteristics are summarized in p < 0.0001) (p < 0.0001), DDF (p < 0.0003) and EOT (p < 0.01) than healthy subjects. The same results were found comparing RD vs. HC groups.TAS ≥ 61 was found in FMS (47.9%) and RD (41.5%) patients, compared to the HC group (2.6%). Subjects in the FMS group reported significant higher scores than HC on TAS total score ( 0.0001) : particup < 0.0001) and HADS-D (p < 0.0001), in the same way as RD patients did compared to HC . Differences in alexithymia and psychological distress did not differ between the FMS and RD groups.58.3% of FMS patients and 48.8% of RD patients showed higher scores on HADS-A (HADS-A ≥ 8) and 66.7% of FMS patients and 51.2% of RD patients reported high scores on HADS-D (HADS-D ≥ 8) while only 5.3 and 13.2% of HC, reported scores above the cut-off on HADS-A and HADS-D, respectively. Patients in the FMS group showed significant higher scores than HC on HADS-A (p = 0.05) than RD patients that is more characterized by the affective dimension of pain (p = 0.013).Questionario Italiano sul Dolore subscales  and VAS scores were significantly higher in subjects with FMS than HC. Moreover, FMS patients experienced a higher pain intensity . In this group, years of education was negatively correlated with DIF  and DDF  and both relationships were maintained while controlling for anxiety and depression. No significant correlations between alexithymia and pain were observed, meanwhile pain and psychological distress showed significant correlations.Correlation analysis conducted between alexithymia and other variables in FMS group  showed ars = 0.453, p = 0.003), QUID-A , VAS  and HADS-A . Furthermore, EOT was positively associated with HADS-D scores . Psychological distress and pain showed significant correlations. While controlling for anxiety and depression in RD group, all the positive correlations between DIF and QUID-S and QUID-A were maintained. No significant associations with demographical variables such as age, years of education or duration of illness were observed in this group.Patients with RD exhibited significant moderate positive correlations between DIF and the QUID-S , QUID-A , VAS , HADS-A  and HADS-D ; DIF scores correlated with VAS  and HADS-D  while EOT is associated with QUID-S , QUID-A  and age . When anxiety and depression were controlled, positive correlations between DIF and VAS and between EOT and age were maintained.Alexithymia was more closely associated with psychological distress and pain in healthy subjects: DIF positively correlated with QUID-S (n = 89), the total TAS score showed that 44.9% (40/89) patients had alexithymia , 38.2% (34/89) patients did not have aleithymia  and 16.8% (15/89) patients were borderline (52 < TAS-20 < 61). Patients in the borderline group were excluded. AL and N-AL groups had no significant differences in age, education and duration of illness , HADS-D (p = 0.007), VAS (p = 0.005) and QUID-S (p = 0.003)  .p = 0.020) and HADS-D (p = 0.027), respectively. Meanwhile, VAS was related to the QUID-S (p < 0.0001) and QUID-A (p = 0.009) and these relationships were maintained when anxiety and depression effects were controlled. No significant relationship was found between alexithymia and pain in AL group, nevertheless, it was found in N-AL group (p = 0.049) and there’s a trend of correlation between DIF and QUID-S (p = 0.066). DIF was negatively correlated with QUID-A (p = 0.05). Concerning psychological distress, HADS-A was negatively related to DIF (p = 0.010) and positively with EOT (p = 0.015); HADS-D was positively correlated with EOT (p = 0.033). All relationships were moderate.Correlation analysis  in the AAL group : EOT wasR2 = 0.53) (p = 0.009). In AL group, VAS was predicted by QUID-S  and the regression model explained the 50% of the variance of the data.In N-AL group, a significant regression model was obtained for VAS as the dependent variable and DIF, EOT, HADS-A, HADS-D and QUID-A as predictors, with a good level of fit with the data ( = 0.53) . HADS-A The main purpose of the research was to investigate the prevalence of psychological distress and alexithymia in fibromyalgia patients, compared to those suffering from arthritis and healthy controls. Moreover, we aimed to describe the role of these variables in pain perception (affective and sensory dimensions) and pain intensity.The results showed higher levels of alexithymia in patients with fibromyalgia, arthritis and other painful rheumatic conditions compared with healthy controls, according to previous research . AlexithIn regard to psychological distress, we found comorbidities between painful chronic conditions and anxious or depressive clinical symptoms, matching previous studies . Our cliIn agreement with Concerning associations between alexithymia and pain or psychological distress in FMS group, we found that alexithymia was not related to pain experience or intensity. This result suggest that lower emotional awareness does not play a primary role in pain perception, and it might be a transitional state related to severity of psychological distress, as other authors already highlighted . In lineStrong correlations between alexithymia, pain and psychological distress were found in RD group. The positive correlation between difficulty in identifying feelings and the different components of pain was maintained, even after anxiety and depression was controlled. This finding suggests that in RD patients, alexithymia plays a more important role in influencing pain, regardless of the presence and severity of comorbid anxiety or depression.With the aim of exploring the potential impact of alexithymia on the intensity and perception of pain, the clinical group (FMS + RD) was divided into patients with or without alexithymia, according to TAS-20 cut-off scores. Alexithymic patients (AL) had higher scores on anxiety, depression, pain intensity and perception than non-alexithymic ones (N-AL), according to previous studies . Two difOur results suggest that while clinical symptoms  are increased in patients with fibromyalgia or RD, the relationship between pain and other variables disappeared. Two separated blocks of significant correlations appeared: on the one side, pain perception and pain experience are associated, on the other side alexithymia is related to negative affects states. This result also suggest that alexithymia may be a state phenomenon that arise from psychological distress and might be investigated with different scales or within longitudinal studies. Meanwhile, when symptoms of psychological distress and alexithymia were subthreshold, correlations with pain experience and intensity became stronger.The present study has some limitations that should be considered. The cross-sectional nature of the study does not allow inferences about the causal relations among the variables. Prospective studies could clarify the relation between alexithymia, pain and emotional distress and its trend over time. Moreover, the use of a self-report measure (TAS-20) to assess alexithymia may not have investigated this construct properly, since it requires subjects to identify and describing affects, which is compromised in alexithymic subjects. The future research could use clinical interviews to assess alexithymia. Moreover, the use of a small sample did not permit the generalizability of the results to the fibromyalgia and arthritis patients population.The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.The studies involving human participants were reviewed and approved by Department of Surgical, Medical and Molecular Pathology, Critical and Care Medicine, University of Pisa. The patients/participants provided their written informed consent to participate in this study.CC conceived the assessment. LM, FM, LB, and CC planned the assessment. LM, FM, and SL contributed to the healthy subjects’ data acquisition. LM, FM, and SL contributed to the patients’ data acquisition. MM and GO contributed to the data analysis. MM, GO, CC, and AG contributed to the data interpretation. LM, FM, GO, RC, PKH, and CC drafted the manuscript. All authors critically revised the manuscript and approved the final version to be published.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.


Many patients suffer from unrelieved pain in hospital settings. Nurses have a pivotal role in pain management. Hence, a nurse-based pain management programme may influence how hospitalized patients experience pain. In this study we investigated hospitalized patients’ experience of pain before and after the introduction of a two-component nurse-based pain management programme.N = 282; Survey 2: N = 283; Survey 3: N = 280) admitted to the four inpatient units  of a university medical center. Data were collected at baseline, before the intervention six weeks after pain management education, and finally immediately after four months of rounding using an interviewer-administered questionnaire adopted from a Brief Pain Inventory and the American Pain Society Patient Outcome Questionnaire.A quasi-experimental design with a separate sample pretest-posttest approach was conducted on a convenience sample of 845 patients (Survey 1: p < 0.05.All the samples had similar sociocultural backgrounds. The proportion of patients who reported average moderate and severe pain intensity in the last 24 h were 68.8% in Survey 1, 72.8% in Survey 2 and then dropped to 48.53% in Survey 3 whereas those who reported moderate and severe pain intensity at the time of interview were 53.9% in Survey 1, 57.1% in Survey 2 and then dropped to 37.1% in Survey 3. The mean pain interference with the physical and emotional function was generally reduced across the surveys after the introduction of the nurse-based pain management programme. These reductions were statistically significant with Though the survey findings must be taken with caution, they demonstrate that the nurse-based pain management programme positively influenced patient-reported pain intensity and functional interference at the university medical center. This shows the potential clinical importance of the programme for hospitalized patients. The occurrence of pain symptoms is one of the primary reasons to seek healthcare in the general population. Pain is often distressing for patients if not adequately managed –3 and maDespite the availability of effective therapies, many patients continue to suffer from unrelieved pain in hospital settings . As a reEven though pain management is the responsibility of every healthcare provider, it is the primary role of nurses. Nursing is an important caregiving situation, and pain management is an integral part of the practice of nursing. Left untreated, pain is considered professional misconduct or a violation of fundamental human rights –3. DespiPrior studies related to pain management were mainly focused on the prevalence of pain –16, the A quasi-experimental design with a separate sample pretest-posttest approach was conducted at Jimma University Medical Center (JUMC) from 1 September 2016, to 15 July 2017.N = 282; Survey 2: N = 283; Survey 3: N = 280) was invited to participate in this study. All patients who were admitted to the four inpatient units at the hospital  were included if they filled the inclusion criteria. Patients had to have been hospitalized for at least 24 h, age ≥ 18 years, and have no known hearing impairment. Initial contact with patients was made through the ward’s head nurse or shifts leader. Participation in the study was voluntary. None of the patients approached declined participation.A convenience sample of 845 patients , we may not be able to keep your pain level at zero. However, we will work very hard with you to keep you as comfortable as possible” [. Staff nurses made subsequent visits every 2 h during the day  and every 4 h at night . During each visit, nurses assured patients of their availability and informed patients when they would return, asked patients to rate their pain levels, and recorded it in the pain log. If necessary, they repositioned the patient and checked for personal needs .A nurse-based pain management programme is an intervention comprised of two components: education (to enhance nurses’ knowledge of and attitude towards pain) and organizational elements (to ensure the systematic monitoring of patients’ pain), with the goal of improving pain treatment. In the educational component, we provided two days of intensive in-service pain management training (16 h of face-to-face training), take-home reading assignments (self-learning), and refresher training four weeks later (8 h) for all nurses in the units. The education programme was arranged in groups and completed between 1 October and 15 November 2016. Each group was comprised of 30–40 nurses. The education sessions were delivered as per the pain management protocol developed by the research team, which was based on Ethiopia’s Federal Ministry of Health (FMOH) pain management guidelines  the WorlMore specifically, staff nurses systematically assessed every patient admitted to the four units up to ten times (every 2 h during the day and every 4 h during the night) in a 24-h period. Unless the patient was unconscious, sleeping or the bed was empty, the pain level was self-rated using the NRS and recorded in the pain log by the nurse. After each pain assessment, the nurse decided if the patient required a change in pain treatment regimen in collaboration with the treating physician, using the WHO pain ladder framework. Based on the collaborative decision, the nurse administered adjusted pain medication by the clock. “By the clock” means that the patient would be given analgesics regularly at a fixed interval of time-based on the known pharmacokinetics of the drug in use and that the next dose of analgesics would be adjusted before the effect of the previous dose had fully worn off. The rounding log was kept easily accessible for the healthcare provider’s review. In addition, nurses participated in the multidisciplinary team rounds and shared patient pain information.Leadership rounding was performed daily by head nurses or clinical leaders (team leaders) and weekly by nursing directors. The leaders’ role was to motivate, facilitate, and provide positive feedback to the nurses. In addition, the head nurse-led weekly staff nurse discussions, and the nursing director led monthly discussions for head nurses and supervisors. Compliance with the rounding protocol was monitored twice weekly by nurse supervisors, using a review of the rounding log and discussion minutes.Pain intensity and interference are regarded as reliable parameters to measure patients’ experiences of pain . To measThe tool was initially translated by healthcare professionals to Afaan Oromo and Amharic; linguistics and non-health care professionals then retranslated back to English. Then, all the translators came together to discuss the translated items. To check how each item was understood, a cognitive interview was conducted with five people of varying backgrounds . FinallyData was first collected at baseline (Survey 1), again six weeks after the educational programme (Survey 2), followed by a third survey immediately after four months of rounding (Survey 3). The data were collected by trained nurses through a structured face-to-face interview that lasted approximately 40–45 min.p < 0.05.All surveys were assessed for missing or incomplete data before being analyzed . Data were analyzed using Statistical Package for the Social Sciences (SPSS) version 20.1 . Descriptive statistics  were calculated for patient characteristics , pain severity, and interference response items. Reduction in the sample means score was calculated by subtracting the mean value of survey 3 from the mean value of survey 1, dividing it by the survey 1 value, and multiplying by 100. Differences between the mean pain intensity and interference scores at baseline (Survey 1), six weeks after the in-service educational program (Survey 2), and immediately after four months of rounding (Survey 3) were analyzed using a one-way Analysis of Variance (ANOVA) with a post-hoc Bonferroni test. The significant differences between the surveys were declared at N = 256; Survey 2: N = 259; Survey 3: N = 267) were analyzed  was generally reduced in the third survey immediately after four months of rounding. On the other hand, the proportion of patients who reported pain in the last 24 h was reduced from 93% in Survey 1 to 87.3% in Survey 3. Similarly, the mean pain interference with physical and affective functions was also greatly reduced. These reductions can be attributed to better pain management following the intervention. This could have prevented patients from severe discomfort and impaired physiological homeostasis such as depressed mood, fatigue, limitation of ADLs, and anxiety , 33. ThePain intensity and interference with function are important parameters in the evaluation of the effectiveness of pain management interventions on the part of patients , 36 and Even though the current study showed a significant positive impact on the mean pain intensity, mean functional interference level, and the proportion of patients who reported pain in the last 24 h (93% in Survey 1 vs. 87.3% in Survey 3), the proportion of patients who reported pain in the last 24 h at the end of intervention was still high when compared with the results of prior prevalence studies in a German teaching hospital (63%) , and in The commonly-used pain medications in the study hospital were tramadol, Non-Steroidal Anti-Inflammatory Drugs (NSAID) , and, rarely, pethidine. However, morphine, the gold standard indicator of adequate pain management, was either not regularly available or not appropriately used. The explanation of medication choice may be linked to various reasons. Those patients who came from districts where community-based health insurance was established and was legally allowed to receive healthcare services free of charge  automatically received all available pain medications in the hospital. However, patients outside this category paid out of pocket. In addition to pharmacological agents, some patients also used nonpharmacological interventions such as massage, prayer, or hot or cold application. On the other hand, the fact that the average monthly income of patients was just over one US dollar per day means that many patients who pay out of pocket may not be able to afford medication or get the medication in a timely fashion. Another possible reason could be the nature of pain. Acute pain is a protective warning signal indicating inflammatory or traumatic tissue damage, whereas chronic pain is a disease per se . Thus, tIn a complex intervention that consists of an educational programme and rounding, it is difficult to attribute the contribution of each specific component to the final results . The eduThe current findings indicate the potential benefits of a nurse-based pain management programme  for hospitalized patients. However, several factors may limit the findings of the current study. One limitation could be attributed to the study design, the use of a non-randomized design without a control group. Initially, we planned to employ a quasi-experimental design with a control group. This was however complicated by a period of public unrest followed by a declaration of a state of emergency, which made it impossible to travel between the intervention and control sites, and our plans to use a control group had to be abandoned. Another limitation is the possibility that nurses may have gained additional knowledge by interacting with medical professionals, thereby improving their practices, resulting in the possibility of physician-initiated pain treatment rather than nurse-initiated pain treatment through consultation. Given all these factors, a simple pre-post study design with three measurement points on separate samples is inadequate for causal inference. Further randomized, multicenter studies are necessary before attributing a nurse-based pain management programme to changes in patient-reported pain intensity and interference. Even though we have no data on the duration of hospitalization or types of procedures the patients had undergone during their hospital stays, it should be noted that this might have influenced the severity of pain.The current study provides empirical evidence that a nurse-based pain management programme (in-service education and rounding) significantly improved patient-reported pain intensity and interference. The instruments used in this survey could be used for monitoring pain management practices at regular intervals to ensure that the changes are sustainable. The findings also imply the need for educational programmes to improve nurses’ technical capacity in in-hospital nursing care. In addition, the phased intervention approach we have used in this study can easily be applied to nursing practices other than pain management, to improve patient-reported outcomes.


Aims: To assess correlation between the Visual Analogue Scale (VAS) pain score and the Oswestry Disability Index (ODI) and which patient factors can influence patient-reported outcome measures (PROMs). This study also aims to assess the response to the sexual function question of the ODI.Methods: Retrospective analysis of 200 consecutive patients undergoing a range of different lumbar spinal procedures between July 2012 and September 2015 was performed. Subgroup analysis was also performed on the 122 patients who underwent microdiscectomy and/or decompression procedures only. Data from notes and clinical letters from the patient's first clinic appointment were collected. In addition to these outcome measures, data were also extracted regarding patients' gender, age, smoking status, alcohol use, employment and mental health status.Results: Significant correlation was found between VAS pain score and ODI (p = 0.002) and between VAS pain score and question 1 of ODI (p = 0.0001). A lower ODI score was reported at time of surgery by those in employment compared to those who are unemployed (p = 0.008). In addition to this, a lower ODI score was reported in those who are self-employed compared to those in employment (p = 0.048) in both cohorts. A significantly higher mean ODI score was shown within the subgroup analysis for current smokers (p = 0.02). None of the other patient factors that were analysed were found to affect PROMs. 65% of patients answered the sexual function question of the ODI.Conclusions: Significant correlation was demonstrated between VAS pain score and ODI. Those who are in employment are far more likely to report a lower ODI score than those who are unemployed at the time of surgery. Self-employed patients were found to have reported a significantly lower ODI score than those who are in employment. Smoking cessation should be encouraged as those who are current smokers may be more likely to report a higher ODI. As 65% of patients decided to answer the sexual function question of the ODI, this supports its further use. Back pain has been defined as the leading cause of disability in the UK , affectiThe Visual Analogue Scale (VAS) and the Oswestry Disability Index (ODI) are two commonly used systems to measure patient-reported outcome measures (PROMs) in spinal patients. The VAS is a unidimensional measure of pain intensity that is widely used for a range of conditions. The ODI, on the other hand, is a condition-specific measure for the assessment of outcomes in spinal pathologies. This tool, developed by Fairbank  in 1980,A range of different patient factors have been shown to also impact these outcome measures. A large proportion of patients who are off work due to their back pain have been found to remain off work even after surgery , so reseThe aims of this study are to assess correlation between the VAS pain score and the ODI and which patient factors can influence PROMs. This study will also assess the response to the sexual function question of the ODI.The setting for this study was a multicultural tertiary neurosurgery centre in a developed western country. Retrospective analysis was undertaken on 200 consecutive patients who underwent a range of different lumbar spinal procedures between July 2012 and September 2015. This patient group was defined as cohort 1. Subgroup analysis for patient factors was also performed on the 122 patients within this cohort who underwent microdiscectomy and/or decompression procedures and this patient group was defined as cohort 2. Inclusion criteria were that the patients were all seen within this time period and were all under the care of and operated on by the same surgeon to ensure consistency of data. All patients with incomplete information regarding their VAS pain score or ODI score were excluded from this analysis and the subsequent data interpretation. When statistical analysis was required, patients were divided into VAS groups based on their level of pain: mild (<4), moderate (5–7) and severe (>8).All of the patients in the main cohort group underwent a range of different lumbar spinal procedures including microdiscectomy, decompression, fusion, nerve root injection and laminectomy. The patients in the subgroup only underwent microdiscectomy and decompression procedures. These operations were performed by the same surgeon who saw them at their first clinic consultation.Data were collected using the notes and clinical letters from the patient's first clinic appointment. PROMs were all taken at this appointment including ODI and VAS pain score. The ODI index, which includes 10 items, is a commonly used outcome measure for reporting how a patient's back or leg pain is affecting their ability to manage daily living. Recent literature has demonstrated that it shows good psychometric properties and is an effective tool for reporting functional outcome following spinal surgery . Each ofIn addition to these outcome measures, data were also extracted regarding patients' gender, age, smoking status, alcohol use, employment and mental health status. This was also obtained from the notes and clinical letters from patients' first clinic appointment.Statistical analysis was performed using the SPSS statistical software . VAS paip value for all data of <0.05 was considered significant.When considering the other patient factors, the same statistical analysis software and method was used. The divisions within each of these groups are demonstrated in p = 0.002 (95% CI 3.83-16.58)). A similar difference was also seen when comparing the moderate group to the severe group, when an average ODI score difference of 11.19 was found (p ≤ 0.0001 (95% CI 6.28–16.10)) ) .p = 0.0001 (95% CI 0.33–0.96)) ) .n = 22) to those who are in public or private sector employment (n = 46). An ODI difference of 6.8 (p = 0.0479 (95% CI 0.06–13.57)) was observed (Employment status was found to have the most significant impact on PROMs. A significantly lower mean ODI score was found when comparing those who are self-employed (observed .n = 68) to those who are unemployed (n = 29). An ODI difference of 12.2 (p = 0.0078 (95% CI 3.24–20.76)) was found, with those who are in employment reporting a lower ODI score  chose to answer question 8, regarding sexual function, of the ODI while 70 patients (35%) chose not to. In the patients who declined to answer this question, this had no bearing on their responses to the rest of the questions as a completion rate of 100% was achieved for the questionnaire .n = 15) compared to those who are in any public or private sector employment (n = 31). There was a mean ODI score difference of 7.2 (p = 0.032 (95% CI 0.91–13.32)) with those who are self-employed reporting the lower scores.The results from the subgroup analysis of cohort 2 also demonstrated a significantly lower mean ODI score in those who are self-employed (n = 46) to those who are unemployed (n = 29). A mean ODI score difference of 11.2 (p = 0.0092 (95% CI 2.98–18.76)) was demonstrated.Furthermore, similarly significant results were also found when comparing those who are currently in any form of employment, including self-employed, (p = 0.02 (95% CI 1.12–14.76)) was shown with those who have never smoked demonstrating the lower mean ODI score.Interestingly, within this subgroup analysis, a significant difference was found when comparing those who currently smoke with those who have never smoked. A mean ODI score difference of 7.9 (As with cohort 1, no statistically significant differences were found when analyzing age, gender and alcohol use.The significant correlation between the VAS pain score and the ODI demonstrated in this study supports their simultaneous use to enable both corroboration of score and further understanding of different sources of pain. The main conclusion from a recent meta-analysis found ‘little correlation between the VAS pain score and ODI’, so extensive further research was recommended in order to assess the correlation between these two measures further . The resDue to the high percentage of those with back pain not returning to work after surgery, further consideration into the reasons behind this is essential. Recent studies have highlighted the need for research to occur into the impact of employment status on PROMs , and thiThe subgroup analysis of the microdiscectomy and decompression patient cohort demonstrated a significantly greater mean ODI score in those that currently smoke. Recent literature has demonstrated increased complication rates in smokers , so thisSignificant attention has also been given to question 8 of the ODI in recent research, providing conflicting information. Response rates of 18% , 36% 1717 and 52The greatest limitation within this study is the inclusion of a range of different lumbar spinal procedures in the main cohort of patients which ranged from nerve root blocks to spinal fusions. As a result of this, the subgroup analysis was performed on the biggest patient population that shared the same operative procedure. The patient cohort size for this study was moderate but was strengthened due to the single surgeon experience that was involved in the analysis in order to maintain consistency of data.This study has demonstrated significant correlation between the VAS pain score and the ODI. This serves to support their simultaneous use in clinical practice. In addition to this, employment status and smoking status have been shown to have a significant impact on PROMs. This should be taken into consideration in clinical practice as additional measures could be put in place in order to try and encourage eventual return to employment and smoking cessation. A response rate of the sexual function question of the ODI of 65% is considered adequate and this encourages its continued use.The authors declare that they have no conflict of interest.


BackgroundHerpes zoster is caused by the reactivation of latent varicella-zoster virus, which promotes acute and chronic pain that may interfere with daily activities and reduce the quality of life. Ultrasound-guided erector spinae plane (ESP) blocks are used for a wide variety of indications in the management of acute, chronic, and postoperative pain. Our aim was to evaluate the efficacy of ultrasound-guided erector spinae plane blocks for the management of pain in herpes zoster.MethodsThe medical records of 34 patients with acute or chronic pain during herpes zoster between May 2017 and June 2018 were investigated at two pain clinic centers. The patients received ultrasound-guided erector spinae plane block: We performed a single injection for the patients having acute pain and a continuous block for the patients having chronic pain. Patient characteristics, block characteristics , the volume of given local anesthetics, the intensity of pain before and after the block procedure using a numerical rating score (NRS) between 0 and 10, and the duration of analgesia were evaluated.ResultsAll patients reported a remarkable and rapid resolution of pain immediately after the block procedure. Median (min-max) NRS score before the block procedure was 9 (4-10). The median (min-max) NRS score was 1.5 (0-7) after the block procedure. The difference was found to be statistically significant (p<0.0001). NRS score after the third month was 1 (0-3); the difference is statistically significant (p=0.002). The median value of analgesia time (min-max) was 18 (3-24) hours.ConclusionOur preliminary experience demonstrated that an ESP block provided sufficient analgesia in acute herpetic pain. A combination of ESP block, pregabalin, and tramadol was also effective within the three-months-period after the block performance. Herpes zoster is caused by the reactivation of latent varicella-zoster virus. Acute severe pain and post-herpetic neuralgia (PHN) is a feared complication of herpes zoster infection. The reported incidence of PHN varies between 5% and 50% depending on the study design, age distribution, and definition -3. TreatUltrasound (US)-guided erector spinae plane (ESP) block is one of the interfascial plane blocks that target the dorsal and ventral rami of the spinal nerves . AlthougThis research was designed as a multicenter retrospective observational study. Local institutional review board (IRB) approval was provided IRB no:2018/31) and written informed consent was obtained from the patients for the performance of erector spinae plane blocks and for the publication of this report. The medical records of patients having herpes zoster  package program. Continuous quantitative data were presented as number, mean ± standard deviation. The paired sample test was applied to non-parametric data for the statistical evaluation of repeated measurements. P<0.05 was considered significant.Forty-two patients met the inclusion criteria and eight patients were excluded due to insufficient data. Fourteen patients were male and 20 patients were female. An ESP catheter was placed in 11 patients and a single injection ESP block was performed in 23 patients. Patient characteristics are summarized in Table Needle insertion levels were at T4 in eight patients, T7 in four patients, T9 in four patients, T6 in three patients, T5 in three patients, T10 in three patients, T12 in three patients, T8 in two patients, T1 and T2 in one patient. There was one lumbar puncture at the L2 level and one bi-level injection at T4-T5 levels. The terminal location of catheter tips was at T4 level in three patients, T5 level in two patients, T10 level in two patients, and the T4, T6, T7, and T9 levels in one patient.All blocks were uneventful and no remarkable complication occurred during and after the performance of the blocks. No clinically apparent motor blockade was observed in any of the patients. No complications were observed regarding long-term catheterization such as signs of infection.The median value of analgesia time (min-max) was 18 3-24) hours. The median (min-max) NRS score before the block procedure was 9 (4-10). The median (min-max) NRS score was 1.5 (0-7) after the block procedure. The difference was found to be statistically significant (p<0.0001). The median (min-max) NRS score after the third month was 1 (0-3); the difference is statistically significant , paravertebral blocks, stellate ganglion blocks, intercostal blocks, cervical plexus blocks, and intra-cutaneous injections. Intrathecal steroid and local anesthetic injections, various peripheral nerve blocks  have also been used . Up to dThe ESP block was first described by Forero et al. for the management of thoracic pain with an injection at the thoracic vertebra level ,10. The ESP blocks were successfully performed in various cases having chronic pain ,12,16-19One advantage of this technique is the achievement of extensive analgesia with a single shot injection. A single injection ESP block provided analgesia for up to 24 hours in our cases. It was shown to provide long-lasting postoperative analgesia up to 48 hours . NeverthAnother advantage of an ESP block is the lower potential risk of mechanical complications, such as nerve damage, pleural puncture, or vessel puncture than its alternatives: paravertebral or intercostal nerve blocks. An ESP block is technically easier to perform without the necessity of multiple injections performed in the intercostal nerve block. ESP blocks have also the advantage of either unilateral or bilateral application. We performed unilateral blocks in patients with herpes zoster requiring unilateral analgesia. The rash of herpes zoster is dermatomal and does not cross the midline, consistent with reactivation from the dorsal root or cranial nerve ganglia. Thus, the possibility of a unilateral blockade should make ESP blocks of choice in Herpes zoster pain. The procedure could be performed at the patient’s bedside or in a block room, either in the sitting or the prone position. Simple monitoring  should be applied, and an intravenous line should be placed for the safety of the procedure.The main limitation of this study is that its retrospective and non-blinded nature may limit us to compare this novel technique to other interventional analgesia methods. Another limitation is that the analgesic efficacy of the ESP block in the three-month-period may be due to the effect of pregabalin and tramadol treatment. On the other hand, we cannot usually conduct a pain study with a control group that no medication or placebo is given due to ethical reasons. Thus, we could not be able to design a study with a control or placebo group to evaluate the efficacy of the ESP block alone. The long-term efficacy of local anesthetics may be related to their desensitization effect but making that differentiation was not possible in our study design.In conclusion, our preliminary experience demonstrated the efficacy of ESP blocks for the management of acute herpetic pain. A combination of ESP block and oral pregabalin with oral tramadol also provided sufficient analgesia in the three-month-period after block performance. An ESP block is easy to apply under ultrasound guidance with an easy sonoanatomy to understand. Adequate analgesia was achieved with the application of a single-injection block or catheter placement in our study. The ESP block may be a promising method for pain management in herpes zoster as an alternative to thoracic paravertebral blocks and intercostal blocks. Comparative studies are needed to assess the superiority of the ESP block to other interventional regional analgesia methods.


Serum levels of IL1β, IL-6, IL-10, IL-17, TNF, CCL-2/MCP-1, IFN-γ, CXCL-10/IP-10, and TGF-β were evaluated in the different Groups. Impairment in thermal or pain sensitivity was the most frequent clinical finding (95.5%) in leprosy neuropathy patients with and without pain, but less frequent in Diabetic Group (88.2%). Previous reactional episodes have occurred in patients in the leprosy and Pain Group (p = 0.027) more often. Analysis of cytokine levels have demonstrated that the concentrations of IL-1β, TNF, TGF-β, and IL-17 in serum samples of patients having leprosy neuropathy in combination with neuropathic or nociceptive pain were higher when compared to the samples of leprosy neuropathy patients without pain. In addition, these cytokine levels were significantly augmented in leprosy patients with neuropathic pain in relation to those with neuropathic pain due to diabetes. IL-1β levels are an independent variable associated with both types of pain in patients with leprosy neuropathy. IL-6 concentration was increased in both groups with pain. Moreover, CCL-2/MCP-1 and CXCL-10/IP-10 levels were higher in patients with diabetic neuropathy over those with leprosy neuropathy. In brief, IL-1β is an independent variable related to neuropathic and nociceptive pain in patients with leprosy, and could be an important biomarker for patient follow-up. IL-6 was higher in both groups with pain (leprosy and diabetic patients), and could be a therapeutic target in pain control.Pain is a frequent symptom in leprosy patients. It may be predominantly nociceptive, as in neuritis, or neuropathic, due to injury or nerve dysfunction. The differential diagnosis of these two forms of pain is a challenge in clinical practice, especially because it is quite common for a patient to suffer from both types of pain. A better understanding of cytokine profile may serve as a tool in assessing patients and also help to comprehend pathophysiology of leprosy pain. Patients with leprosy and neural pain ( Despite ongoing efforts to eradicate leprosy in Brazil, it remains an endemic disease and a public health challenge . Nerve tMycobacterium leprae, an intracellular pathogen that preferentially infects macrophages and Schwann cells.Leprosy is a chronic infectious disease caused by Mycobacterium leprae alters mitochondrial glucose metabolism in Schwann cell (SC). This affects the complicated modulation of Schwann cell and axons, resulting in a reduction of axonal metabolism, demyelination, and loss of axons   and Diabetes Outpatient Clinic of Pedro Ernesto University Hospital . Medical records and a database of leprosy neuropathy patients evaluated at ASA from January 1998 to December 2017 were also the source of data collection, together with data regarding histopathology of nerve biopsy to determine neuropathy etiology. During the aforementioned period of time, 662 biopsies were performed. Within the biopsied patients, 311 were diagnosed with leprosy. Out of the 311 leprosy patients, 89 had pain during the evaluation prior to nerve biopsy, while 222 had no pain. All the biopsied patients having confirmed leprosy neuropathy in combination with neural pain were selected to the study. The other patients were selected to take part into two comparative groups, namely, one group consisting of painless leprosy neuropathy patients, the other group consisting of patients with diabetic neuropathy in combination with neuropathic pain. The total number of patients was divided up into three groups, as follows:Group A: Leprosy Neuropathic Pain Group (89 patients); Group B: Painless Leprosy Neuropathy Comparative Group (50 patients); and Group C: Diabetic Neuropathic Pain Comparative Group with Type II Diabetes Mellitus (23 patients).Patients with comorbidities known to cause peripheral neuropathy such as rheumatologic diseases, alcoholism, hypothyroidism, diabetes (except Group C patients), B12 hypovitaminosis, HIV or viral hepatitis, patients in corticosteroid treatment or in reaction, further to patients with incomplete medical records or without a laboratory-stored blood sample were excluded from this study. Accordingly, 106 patients were excluded. Out of them, 67 patients were excluded from Group A, 33 patients were excluded from Group B, and 6 patients from Group C. After applying the exclusion criteria, 56 patients have remained in the study: 22 in Group A; 17 in Group B; and 17 in Group C.The following flowchart describes the methodology used in the present study . As soonNeuropathic pain was defined as pain caused by damage or disease affecting the somatosensory nervous system, according to International Association for the Study of Pain. Neuropathic pain diagnosis was based on European Federation of Neurological Societies (EFNS) guidelines . PatientInformation on the neurological examination performed prior to nerve biopsies was gathered from medical records. The type of pain , pain intensity  , and paiType 1 reaction or reversal reaction (RR) is a type IV delayed hypersensitivity reaction characterized by ulcerative, red, swollen skin lesions followed by fever . Type IIData were collected from examinations performed via a 4-channel Nihon-Koden-Neuropack S1 equipment, in accordance with standard procedures . AmplituAccording to the results, the following six pathophysiological classifications were determined:No injury, or normal: when the findings were within the reference values;Axonal injury: when there was a sharp decrease in compound muscle action potential (CMAP) amplitude (more than 30% of the lower limit), or a moderate decrease with a slight reduction in conduction velocity , or a slight prolongation of latency ;Demyelinating lesion: when there was a sharp decrease in conduction velocity , or an evident prolongation of CMAP latencies  with slightly reduced amplitude including the presence/absence of demyelination markers such as conduction block (CB) and temporal dispersion (TD);Demyelinating lesion with secondary axonal damage, or mixed lesion: when there was either axonal or demyelinating impairment, i.e., sharp decrease in amplitudes with greatly reduced velocities and quite prolonged latencies, further to demyelination markers, such as CB and TD, with a sharp reduction in amplitudes;Not fulfilled: sensory or motor alterations that did not fit the criteria above; andUnclassified/unresponsive: in case of absent sensory and motor responses .The clinical and neurophysiological diagnosis of neuropathy was defined as a clinically or neurophysiologically detectable impairment of sensory and/or motor nerve.The selection of which sensory nerves to be biopsied in each patient was based on the findings regarding their clinical and neurophysiological involvement. Nerve biopsies were performed in accordance with institutional protocol and leprosy etiology in pure neural leprosy patients, and confirmed by Antunes et al. .Serum samples used to measure cytokine concentrations were stored at −70°C, according to Good Laboratory Practices. Serum concentrations of IL1-β, IL-6, IL-10, IL-17, TNF, CCL-2/MCP-1, IFN-γ, CXCL-10/IP-10, and TGF-β in the samples were evaluated via ELISA, as specified by the manufacturer . Serum levels were measured in picograms per mL (pg/mL).All the collected patient data were recorded on the database spreadsheets commonly used in outpatient clinic. Data analysis was performed using SPSS statistics 22 program. A descriptive analysis of explanatory variables described below was performed. Comparisons between groups were carried out by means of Chi-square and Fisher's tests for categorical variables, and Kruskal–Wallis test for continuous variables. A logistic regression using a stepwise method was performed to evaluate any possible pain variables.Explanatory Variables:The following variables were analyzed:Demographic data: age (in years), gender , and ethnicity ;Clinical data: clinical form of leprosy (in groups A and B) according to Ridley and Jopling  criteriaNerve conduction study: lesion pattern ;Cytokine and chemokine serum concentrations: The concentrations of IL1-β, IL-6, IL-10, IL-17, TNF, CCL-2/MCP-1, IFN-γ, CXCL-10/IP-10, and TGF-β were recorded in picograms per mL (pg/mL).Our research was carried out in compliance with the International Compilation of Human Research Standards, and approved by the Ethics Committee of Oswaldo Cruz Foundation. Approval number: 2.972.967 CAAE 94630718.7.0000.5248. All patients have signed informed consent before any procedure.Demographic data of the three Groups are described in p = 0.019). Neural thickening was noted in both Groups at a similar frequency. Out of patients from Group A, 18 (81.8%) had neuropathic pain and 4 had neuritis  from Group A and none from Group B, a statistically significant finding , followed by pain similar to an electric shock (40.9%). Pain was considered severe (intensity higher than 7) in 81% of all cases; and most of patients have experienced pain in more than 2 nerves according to their neuroanatomical distribution. These findings are summarized in p < 0.00001), whereas there was no statistically significant difference between Groups A and B . Motor impairment was noted in 59.1% of Group A and 47.1% of Group B (p = 0.455)  were present in 95.5% (21 patients) of Group A, 88.2% (15 patients) of Group B, and 70.6% (12 patients) of Group C. Large fibers involvement (characterized by impaired vibration sensitivity) was noted in 18.2% (4 patients) of Group A, 11.8% (2 patients) of Group B, and 100% (17 patients) of Group C. The involvement of large-caliber fibers was significantly higher in Diabetic Group (= 0.455) .p = 0.001). IL-1β concentrations were significantly higher in Group A than in Groups B and C (p = 0.0001 in both comparisons). No difference was noted between Groups B and C (p = 0.46).Mean values for IL-1β, TNF, TGF-β, and IL-17 cytokine concentrations were higher in the Group of leprosy neuropathy in combination with neural pain than in the other Groups. Regarding mean values, IL-10 concentrations in Group A were lower than in Groups B and C, with a statistically significant difference between Groups A and C (p = 0.041). Even so, no difference was found between Groups A and C (p = 0.75); and TNF was higher in Group A than in Group B. There was no statistical difference between Groups A and B (p = 1.0), however Groups A and C were significantly different (p = 0.02). Mean values of IL-17 were significantly higher in Group A than in Group B (p = 0.01). However, there was no statistical difference in the other group comparisons, although CCL-2/MCP-1 mean values had been higher in Group C than in the other Groups. There was a significant difference when comparing CCL2/MCP-1 values in Group C to Groups A and B (p = 0.001 and p = 0.01 respectively). No difference was noted between Groups A and B; but the differences between IFN-γ values in Group C (p = 0.0001) were higher and significant when compared to the ones in Group A.IL-6 concentrations were higher in patients with diabetic neuropathy in combination with neuropathic pain, further to those with leprosy neuropathy in combination with neural pain in a comparison with leprosy neuropathy patients without pain. This difference was considered statistically significant (p = 0.02) and Groups A and C (p = 0.0001). The opposite have occurred with regard to TGF-β concentration levels, which were higher in Group A and significant between both Groups A and B (p = 0.01), further to Groups A and C (p = 0.0001). CXCL-10/IP-10 concentrations were higher in Diabetes Group, intermediate in Group B, and lower in Group A. These data were statistically significant between Groups A and B , as demonstrated by a different kind of study , 5, 34. Previous reactional episodes were not noted in Painless Neuropathy Group, but in the Group of leprosy neuropathy in combination with neural pain, which consists mostly of multibacillary patients. Many authors believe that the reactional episodes accompanying leprosy are among the risk factors for neuropathic pain , 32, 37.In the present study, during neurological examination, small fiber neuropathy was the most frequent finding among leprosy patients. These data are similar to the ones previously described , 32. UnmAs to nerve conduction studies, despite the absence of statistically significant differences between the groups with and without pain, there was a tendency toward prevalence of demyelinating form in the group with pain. Jardim et al.  have desMany studies have shown that cytokines are higher in leprosy type I and II reactional episodes, defined as systemic inflammatory complications in leprosy. One study suggests that TNF and IL-10 could possibly predict the occurrence of type I and II reactions, respectively, while increased IL-1β and IFN-γ might also predict the occurrence of both reactional types acting as biomarkers . The incAgain, the present study ascertains that IL-1β is an independent variable related to neural pain group. Although most patients in the present study have neither presented with acute neuritis nor experienced acute reactional episodes, a process of silent neuritis cannot be ruled out (4/56 patients presented with neuritis). Proinflammatory cytokines such as TNF and IL-1β are effective to directly stimulate and sensitize Aδ fibers and type C fibers . In ratsMoreover, increased levels of TNF, TGF-β, and IL-17 in leprosy and neural pain patients have also been detected. One report has shown that, in leprosy, TNF and TGF-β induce apoptosis in Schwann cells, with a consequent damage to peripheral nerve . AlthougIL-17 levels were increased in Pain Group. The association between higher IL-17 and pain has been previously described in relation to both nociceptive  and neurLower levels of IL-10, an anti-inflammatory cytokine, were noted in the group of patients with leprosy neuropathy in combination with neural pain. IL-10 causes the negative regulation of proinflammatory cytokines , presentIL-6 has been related to postherpetic neuralgia, neuropathic pain secondary to disc herniation, and the carpal tunnel syndrome , 13. It Increased CCL2/MCP-1 and CXCL-10/IP-10 levels were noted in diabetic patients with neuropathic pain. Studies indicate that CCL-2/MCP-1 may regulate the excitability in neurons of dorsal ganglion root (DRG) as it is associated with the development of chronic, painful hypersensitivity states , 61. A sFurthermore, the present study reaffirms that the immunological profile of patients with neural pain has shown an increased level of pro-inflammatory cytokines. IL-1β is an independent variable related to neural pain and may be an important biomarker for patient follow-up. The lack of differences in neurological examination may indicate that the cytokine profile is more closely related to pain than to nerve damage itself.Regarding serum levels comparison within the different groups, increased levels of IL-6 were noted in patients with neural pain secondary to leprosy and type II diabetes mellitus in combination with neuropathic pain, indicating that IL-6 may be a pain biomarker. Anti-IL-6 drugs have been investigated as possible targets to pain control. A new drug called tocilizumab has been used in cases of inflammatory arthritis and acute optic neuritis followed by inflammatory and neuropathic pains, respectively , 64. An Finally, the fact that this is a retrospective study is an important limitation. Many patients were excluded due to lack of data or absence of blood samples, which greatly reduced the sample of patients. Moreover, the fact that data were collected from assessments of different examiners is another limitation.In conclusion, further prospective studies with larger numbers of patients are needed to confirm the role of cytokines in neural pain. However, this study highlights a possible biomarker for follow-up and brings new perspectives in the management of patients with neural pain in leprosy.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by the Oswaldo Cruz Foundation. The patients/participants provided their written informed consent to participate in this study.DA, ES, MJ, and RP formulated the study questions. DA, MJ, RP, MH, and JV designed the study protocol. DA, RP, JV, RC, MH, IP, LG, ES, and MJ conducted the experiment. ES, MJ, and RP supervised the study. DA and MH analyzed the data. DA drafted the manuscript. ES, MJ, and RP revised the manuscript. All authors contributed to the interpretation of the data, read and approved the final version for publication and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.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.


Helicobacter pylori-related peptic ulcer disease . 25(OH)D was inversely correlated to spontaneous/brush-evoked pain. Spontaneous pain was positively correlated to VZV IgM. Based on the receiver operator characteristic curve, cutoffs for 25(OH)D to predict spontaneous and brush-evoked pain were 67.0 and 169.0 nmol/L, respectively. A prospective, longitudinal study is needed to elucidate the findings.Hypovitaminosis D (25-hydroxyvitamin D (25(OH)D) <75 nmol/L) is associated with neuropathic pain and varicella-zoster virus (VZV) immunity. A two-part retrospective hospital-based study was conducted. Part I (a case-control study): To investigate the prevalence and risk of hypovitaminosis D in postherpetic neuralgia (PHN) patients compared to those in gender/index-month/age-auto matched controls who underwent health examinations. Patients aged ≥50 years were automatically selected by ICD-9 codes for shingle/PHN. Charts were reviewed. Part II : To determine associations between 25(OH)D, VZV IgG/M, pain and items in the DN4 questionnaire at the first pain clinic visit of patients. Independent predictors of PHN were presented as adjusted odds ratios(AOR) and 95% confidence intervals (CI). Prevalence (73.9%) of hypovitaminosis D in 88 patients was high. In conditional logistic regressions, independent predictors for PHN were hypovitaminosis D , malignancy  and  Vitamin D is essential for musculoskeletal health in humans. The major circulating form of vitamin D is serum 25-hydroxyvitamin D (25(OH)D)—the main storage form. Currently, serum total 25(OH)D is considered to be the best marker of vitamin D status among the possible markers . HoweverHerpes zoster (shingles) is a common infectious disease resulting from reactivation of latent varicella-zoster virus (VZV). Patients with shingles suffer from herpetic pain which generally subsides within four weeks. Approximately 8%–24% of all zoster patients develop chronic herpetic pain known as postherpetic neuralgia (PHN) which lasts longer than 90 days after rash onset ,22,23. APHN is a peripheral neuropathy PHN patients experience various spontaneous and/or brush-evoked pain  . The DouThe study was conducted in accordance with the Declaration of Helsinki. This retrospective study was approved by the Institutional Review Board of the Chi Mei Medical Center in Tainan, Taiwan (IRB-10606-002). Patients’ data in this study were drawn from the electronic medical database of Chi Mei Medical Center which is a 1200-bed tertiary referral center in Tainan, Taiwan.During their first pain clinic visit, zoster patients routinely completed the DN4 questionnaires  and received evaluation of their average daily spontaneous pain severity and the worst spontaneous pain on an 11-point numeric rating pain scale   Supplem. Brush-eIn this retrospective study, zoster/PHN patients aged ≥ 50  receivinPhysicians (JYC and YTL) signed a patient confidentiality agreement before chart reviews. Each chart was reviewed for the inclusion and exclusion criteria. We included PHN patients who received a prescribed analgesic, anticonvulsant, or antidepressant or treatments by physicians for persisting pain ≥ 3 months and shorter than two years after zoster rash onset  as well Age, gender and index-month are common confounders of vitamin D status . ConditiThe present study was a two-part retrospective hospital-based study including Part I (a case-control study) and Part II . Using data from the electronic medical database of our hospital, we included automatically selected PHN patients and the gender/index-month/age-auto matched controls (non-PHN cases) in the case-control study. In the cross-sectional analysis, we included participants who were PHN patients of the case-control study.Helicobacter pylori-related peptic ulcer disease was identified by ICD-9 530–534 and confirmed by positive findings on either hospital gastroduodenoscopy records or a self-reported gastroduodenoscopy history with prescriptions for the disease within one year prior to shingles outbreak [Hypertension/diabetes mellitus diagnosis was defined as patients who had ICD-9 codes for hypertension (ICD-9 401-405)/diabetes mellitus (ICD-9 250) and received a prescribed medication for hypertension/diabetes mellitus. Malignancy, autoimmune diseases, and chronic liver disease diagnosis were defined as patients who had ICD-9 code  and received treatments by physicians for the diseases. Patients with chronic kidney disease were those who had ICD-9 585 and received dialysis regularly. outbreak .Automated immunoassays are currently popular methods for measuring the circulating level of 25(OH)D. At our institute, a fasting blood sample was drawn in the morning from the testing subjects. Once the serum was separated, it was kept frozen at a temperature of −70℃ until analysis. Serum 25(OH)D concentrations were measured by ARCHITECTi2000  (Chemiluminescent Microparticle Immuno Assay)  every weSerum samples of PHN patients were routinely obtained for the VZV IgG and IgM antibody tests using enzyme-linked immunosorbent assay (ELISA) kits manufactured by Euroimmun   and TECAIn this study, the estimated rate of hypovitaminosis D in patients versus the controls was 70% versus 50% . Therefon = 64) and patients aged 50–59 years (n = 24). Univariate logistic regression analysis was used to examine the associations between all selected predictors and PHN development in this study. A univariate association (p < 0.10) with PHN was included in the conditional multiple logistic regression model. Independent predictors for PHN were identified in the conditional multiple logistic regression model by gender, index month, and age  match. Furthermore, patients were divided into two groups according to 25(OH)D levels: hypovitaminosis D (25(OH)D < 75 nmol/L) and sufficiency of vitamin D (25(OH)D ≥ 75 nmol/L). All of the demographic and clinical variables were compared between patients with sufficient-vitamin D and those with hypovitaminosis D.Data processing and statistical analysis were performed using SAS statistical software . The significance of difference among continuous data between the two groups was determined by student’s t-test. Chi-square test or Fisher exact test was used to test the differences in categorical variables between the two groups. The risk of PHN was presented as an odds ratio (OR) and 95% confidence intervals (CI). Patients were divided into two groups according to age: patients aged 60years or older D, VZV Ig) and severity of pain where appropriate. The correlation between clinical variables and severity of pain was considered to be clinically significant if the rho>0.3 . AccordiA total of 119 PHN medical records were selected for review. Three patients were considered to experience other causes of chronic pain, while 19 patients were determined to suffer from zoster-associated pain which was defined as herpetic pain beyond 30 days but less than 90 days. Three patients were excluded due to incomplete records. In total, 25 patients were excluded after medical record review. Additionally, six elderly patients were excluded because of no age-matched controls .Conditional Logistic Analysis for the Predictors of Postherpetic Neuralgiap = 0.005; <0.001). Furthermore, PHN patients had higher prevalence of diabetes mellitus , malignancy  and Helicobacter pylori-related peptic ulcer disease  compared to that in the controls. There were no significant differences inbody mass index and the prevalence of hypertension, autoimmune diseases, chronic liver and kidney disease between the two groups.The demographic characteristics of 88 patients and 264 controls are shown in p < 0.001), malignancy  and Helicobacter pylori-related peptic ulcer disease .Although four risk factors for PHN were identified in univariate conditional logistic analysis, only three risk factors remained after conditional multivariate logistic analysis, including hypovitaminosis D  1.73–5.61, p = 0.016; 0.005; 0.021; 0.007) , a lower vitamin D supplementation rate (1.5%) and greater spontaneous/brush-evoked pain intensity , compared to those in patients with sufficient vitamin D   .p = 0.002) and VZV IgM . Brush-evoked pain was correlated to the serum level of 25(OH)D . The other Spearman correlation coefficients were ≤ 0.3 indicating no clinical significance (Data not shown).In The cutoffs for serum 25(OH)D concentration to predict spontaneous pain and brush-evoked pain were 67.0 nmol/L (26.8 ng/mL)  and 169.0 nmol/L (67.6 ng/mL) , respectively. The cutoff for IgM titer to predict spontaneous pain was 0.60 with a sensitivity of 58.7% and a specificity of 76.2%. Based on the AUC values, we found that serum 25(OH)D status  and IgM titers (0.689) were good predictors for pain in PHN a–c.p < 0.001; p = 0.002). Although vitamin D-deficient patients (< 50.0 nmol/L) had greater proportions of painful cold and brush-evoked pain compared to those in vitamin D-insufficient patients , no statistically significant difference in brush-evoked pain was found between the two groups. Possibly, it was due to the small case number in the group with deficiency.  had a score greater or equal to 4 in the DN4 questionnaire. In10items of the DN4 questionnaire, patients with vitamin D ≤ 67.0 nmol/L had greater proportions of painful cold and brush-evoked pain compared to those in patients with vitamin D > 67.0 nmol/L  in subjects living on similar latitudes in our country located in the subtropical region . The pre disease , all of  disease , lack of disease ,45, indi4.1% in s disease , leading disease . It rais disease ,30,35,47Helicobacter pylori-related peptic ulcer disease independently predicted PHN in conditional multiple logistic analysis. Because the pathogenesis of PHN includes neuronal excitability and persistent viral infection-induced neuroinflammation [In Part I study, hypovitaminosis D, malignancy and ammation ,49, therammation  and astrammation . Second,ammation ,52. ThirHelicobacter pylori-related peptic ulcer disease [PHN patients experience various spontaneous pain and brush-evoked pain  . Signifi disease , both haIn Part II study, hypovitaminosis D was found to be associated with increased neuropathic pain in PHN patients. Vitamin D is a neuroactive steroid that may mediate pain processes by modulating several signal transduction systems. Patients with statin-induced musculoskeletal pain often have low vitamin D levels . StatinsIn the current study, the cutoffs for 25(OH)D level to predict spontaneous pain and allodyniawere67.0 and 169.0 nmol/L, respectively. The difference in thresholds is consistent with the finding of a previous experimental study showing different thresholds for eliciting pain, allodynia, and hyperalgesia in rats . In 88 PThe positive rate of VZV IgM in shingles ranges from 10% to 70% . The posIn terms of limitations, we did not assess sun exposure time, sunscreen use, daily activity, and vitamin D-rich food consumption , althougPHN patients aged 50–85 had a high prevalence of hypovitaminosis D which was associated with increased spontaneous and brush-evoked pain. PHN patients with hypovitaminosis D had greater pain, higher VZV IgM titers, and a lower vitamin D supplementation rate than those in subjects without the condition. The cutoffs for 25(OH)D to predict spontaneous pain and brush-evoked pain were 67.0 and 169.0 nmol/L, respectively. Patients with vitamin D ≤ 67.0 nmol/L had significantly greater proportions of painful cold. Spontaneous pain was also correlated to VZV Ig Mtiters. The cut-off for IgM to predict spontaneous pain was 0.60. Further prospective, longitudinal studies are warranted to confirm these findings.


Internal fixation with volar locking plate (VLP) was widely adopted as a first-line choice in treatment of distal radius fracture (DRF).μg/h, and 77 received 13 mg codeine plus 200 mg ibuprofen twice per day for pain management. Visual analog scale (VAS) scores of pain at rest, daily activity, and rehabilitative exercise were measured, respectively, every week according to the experiences of the past week in the initial six weeks after surgery. Functional outcomes including range of motion (ROM) for extension, flexion, pronation, supination, ulnar and radial abduction, the disabilities of arm, shoulder, and hand (DASH) score and the validated patient rated wrist evaluation (PRWE), and grip strength were collected at one, three, and six months after surgery. Total 315 patients with distal radius fracture receiving VLP fixation were included for analysis in this study. The rehabilitation protocol was started immediately after surgery for all patients. During the initial two weeks after surgery, 149 patients received 200 mg celecoxib twice per day, 89 received buprenorphine transdermal patch at 5  We showed that patients receiving transdermal buprenorphine and codeine/ibuprofen had decreased VAS scores during rehabilitative exercise, better compliance to the rehabilitation program, and thus faster functional recovery. We recommend transdermal buprenorphine or codeine/ibuprofen for pain management during rehabilitation after distal radius fracture stabilized with VLP. Distal radius fractures are a common type of fractures, affecting more than 1% of the overall population [Kirschner wire (K-wire) and open reduction with VLP are the two most common surgical fixation techniques used to manage distal radius fractures. Several clinical trials have shown faster recovery of hand and wrist function with volar plating compared with K-wire or external fixation , 3. As aK-wire fixation commonly requires postoperative immobilization to prevent secondary displacement. Hence, early mobilization and faster functional recovery are believed to be the most important advantage of VLP fixation , 7. The The work has been reported in line with the STROCSS criteria .https://www.researchregistry.com). The registry number is researchregistry4070.The study was approved by the Ethics Committee of First Affiliated Hospital of Wenzhou Medical University. Informed consent was obtained from all participants and all methods in this study were in accordance with the Declaration of Helsinki. The study is registered in Research Registry  treated with VLP fixation from February 2014 to February 2016 were finally enrolled into this study. Exclusion criteria were age below 18 year (n=21); unwilling to participate (n=84); any concurrent injury to the upper limbs (n=23); previous wrist fracture on any side (n=7); preexisting inflammatory joint condition (n=9); professional athlete (n=3); any concurrent fracture (n=37); chronic pain or receiving pain medication (n=33); a distal radius fracture for which, in the surgeon's judgment, fixation of fracture fragments could not be achieved to allow early mobilization (n=31). Finally, 315 patients completed the six-month follow-up. The basic characteristics were summarized in The standard volar-radial approach over the flexor carpi radialis tendon was chosen. Reduction was achieved by temporary K-wires and the fracture was then stabilized with DVR® volar plate (Zimmer Biomet). No case received bone graft in this study. Pronator quadratus repair was performed in all cases. Patients were discharged from our hospital on second to fourth postoperative day. All patients received the same standardized home exercise therapy and written physiotherapy advice. The rehabilitation protocol started immediately after surgery. The rehabilitation protocol was designed based on the previous literature , 12, 13 μg/h; 13 mg codeine plus 200 mg ibuprofen twice per day. The duration of pain medication was two weeks after surgery for all three protocols. Patients were grouped based on the received pain medication .Due to the lack of evidences, the pain management protocols were designed based on our previous experiences and currently available literature on chronic pain management , 15. TheVisual analog scale (VAS) score ranges from 0 (no pain) to 100 mm (worst pain possible). VAS score was measured every week according to the patient's experience of average pain in the past week in the initial six weeks after surgery. The VAS scores in three different scenarios  were measured.Range of motion (ROM) for extension, flexion, pronation, supination, and ulnar and radial abduction was documented for both the healthy and the injured wrist using a goniometer. The ROM in this study was presented as a percentage calculated according to the ROM of uninjured side. Because there are interindividual variation in mobility, the ROM of the uninjured side was defined as the standard value and set as 100%. The disabilities of arm, shoulder, and hand (DASH) score are a 30-item self-report questionnaire  which provides a general measure of physical function and symptoms in people with disorders of the upper limb. The validated patient rated wrist evaluation (PRWE) rates wrist function in two equally weighted sections concerning the patient's experience of pain and disability. The outcome is a score out of 100 (with 100 indicating the worst condition). Grip strength was measured with the elbow flexed at 90 degree and the forearm in neutral rotation. Values are expressed as percentages of the values of the contralateral hand. The PRWE, DASH, grip strength, and ROM of wrist were collected at one, three, and six months after surgery.Total 351 patients with acute distal radius fractures treated with VLP fixation from February 2014 to February 2016 were enrolled into this study. Finally, 315 patients completed the six-month follow-up. Among patients who completed the entire follow-up, 149 patients received celecoxib, 89 patients received transdermal buprenorphine, and 77 patients received codeine/ibuprofen during the initial two weeks postoperatively. Loss to follow-up occurred in 17, 10, and 9 patients of celecoxib, transdermal buprenorphine, and codeine/ibuprofen groups, respectively. The basic characteristics were summarized in P < 0.05) within two weeks postoperatively. Celecoxib at 200 mg per day showed inferior effects in pain management during rehabilitative exercise compared with the other two groups. Consistently, transdermal buprenorphine and codeine/ibuprofen increased the patients' compliance to the rehabilitation program. The percentage of patients in celecoxib group who completed the rehabilitative program was the lowest within the initial two weeks. The difference in VAS scores at rehabilitative exercise in Week 6 was statistically significant (P = 0.04) but not clinically relevant.Shown in As expected, the recovery of celecoxib group was significantly slower than that of the other groups . PRWE anThe concept that early rehabilitation after fractures could accelerate functional recovery has been well-established among orthopedic surgeons and therapists. The rehabilitation program of distal radius fractures stabilized with VLP was recommended to be started within one week by multiple studies , 9. HoweThere were three in-place protocols using celecoxib, transdermal buprenorphine, and codeine/ibuprofen respectively. All three protocols showed satisfactory pain relief at rest and daily activity with no significant difference. However, patients receiving buprenorphine transdermal patch and codeine plus ibuprofen experienced less pain during rehabilitative exercise compared with those receiving celecoxib. As a result, transdermal buprenorphine and codeine/ibuprofen groups had a significantly faster recovery compared with celecoxib group.The duration of pain medication was two weeks after surgery for all three protocols. The VAS scores of Week 3 at rest, daily activity, and exercise were all quite mild, indicating it was not necessary to further prolong the duration of pain medication. It is still not clear whether the duration could be shortened.Several limitations should be considered when interpreting the study results. As all observational studies where the treatment is not randomly assigned, unmeasured confounding factor could possibly exist and bias the study results. In clinical setting, patients with more pain are commonly given a stronger pain medication regimen. The different physicians also have different preferences on postoperative pain management. In addition, participants of this study were aware of their treatment and their expectations of pain relief could be different. In addition, we did not collect the information of opioid and NSAID utilization and thus was unable to provide more useful information. Finally, this study only addressed the comparative effectiveness of the three in-use protocols in our hospital. We did not make a comparison to no analgesics.We recommend transdermal buprenorphine or codeine/ibuprofen for pain management during rehabilitation after distal radius fracture stabilized with VLP.


Opioids are commonly used for the management of postoperative pain, but their use is limited by important adverse events, such as respiratory depression and the potential for addiction. Multimodal opioid-sparing analgesia regimens can be effectively employed to manage postoperative pain and reduce exposure to opioids. Gabapentinoids  represent an attractive class of drugs for use in multimodal regimens. The American Pain Society recommends the use of gabapentinoids during the perioperative period; however, evidence to inform such a recommendation is unclear.I2 index.We will conduct a systematic review and meta-analysis of randomized clinical trials evaluating the use of systemic gabapentinoids, in comparison to other analgesic regimens or placebo in adult patients undergoing surgery. We will search MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), the Web of Science, and ClinicalTrials.gov databases for relevant citations. Our primary outcome will be intensity of postoperative acute pain (12 h). Our secondary outcomes will be postoperative pain intensity at 6, 24, 48 h, and 72 h, cumulative dose of opioids administered within 24, 48, and 72 h following surgery, the length of stay, chronic pain, and adverse events. Two investigators will independently select trials and extract data. We will evaluate the risk of bias of included trials using the Cochrane risk of bias tools. We will represent pooled continuous data as weighted mean differences and pooled dichotomous data as risk ratios with a 95% confidence interval. We will use random effect models and assess statistical heterogeneity with the Our study will provide the best level of evidence to inform the effect of gabapentinoids in the management of postoperative acute pain.CRD42017067029PROSPERO The online version of this article (10.1186/s13643-018-0906-3) contains supplementary material, which is available to authorized users. Because of their numerous adverse events  and their potential for addiction, reducing opioid administration is a core element in the domain of postoperative pain management –3. In thThe American Pain Society supports the use of gabapentinoids as a part of multimodal analgesia . HoweverOur primary objective is to evaluate the analgesic effect of gabapentinoids in perioperative care in adult surgical patients compared to placebo or any other analgesic regimen. Our secondary objectives are to assess its effect on the opioid use, the length of stay and the incidence of chronic pain. We will also evaluate the incidence of adverse events.http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017067029). The manuscript reporting the results of the systematic review will be written following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P2015) recommendations [Our study is a systematic review and meta-analysis of randomized controlled trials and our protocol was prepared according to the methodological recommendations of the Cochrane Handbook for Systematic Reviews and Meta analyses . This prndations .Our primary outcome measure is postoperative pain intensity 12 h after surgery or at the time of hospital discharge if earlier. We decided to prioritize dynamic (during movement) pain over rest pain if both are reported, because this type of pain is more relevant for patients and it is associated with better recovery . We seleOur secondary outcome measures are the postoperative pain intensity at different time points , the cumulative dosage of intravenous (IV) morphine equivalent (ME) over the first 24, 48, and 72 h following surgery, and the lengths of stay . For the measure of pain intensity, if data at the specific time point are unavailable, the following intervals will be considered: 0–6 h, 7–12 h (primary outcome), 13–24 h, 25–48 h, and 49–72 h. We will also evaluate the incidence of postoperative chronic pain (defined as lasting for 3 months or more). In case the incidence of chronic pain is not reported but the incidence of complex regional pain syndrome (CRPS) is, this data will be used. The incidence of postoperative adverse events such as dizziness, fall or ataxia, delirium, addiction or abuse, visual disturbance, respiratory failure (respiratory insufficiency or respiratory depression), and nausea and/or vomiting (PONV) will be considered.We will include trials comparing the systemic use of gabapentinoids  to a placebo or any other type of drug used for the management of perioperative acute pain. Our study population will be adult patients (more than 80% of patients are 18 years of age or older) undergoing elective or emergent surgery under any type of anesthesia. To be included, trials should have studied the perioperative use of gabapentinoids (defined as being started at any moment between 1 week prior to and 12 h after surgery) and have evaluated at least one of our outcomes of interest. We will exclude trials comparing the use of gabapentinoids to regional analgesia . Cross-over trials and trials including patients already receiving gabapentinoids for a chronic pain condition will not be considered for inclusion. We will use no language restriction.We will search MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and ClinicalTrials.gov databases for randomized control trials published to date. We will generate Medical Subject Headings (MeSH), Emtree terms, and free text words to identify articles. We will divide vocabulary themes into three main text term categories: 1) perioperative (surgery or anesthesiology), (2) gabapentinoids , and (3) RCTs. The search strategy will be reviewed by an information specialist, and we will validate its quality according to PRESS 2015 guideline . Bibliog perioperWe will create a standardized data abstraction form with Microsoft Excel and carry out a pilot test on the first ten trials. Two reviewers (MV and XS) will then independently extract data. A third reviewer (AFT) will be consulted in cases of disagreements, and all reviewers will be involved in reaching a common consensus. We will contact the authors when relevant information is missing.We will extract the following study characteristics: years of publication, countries, number of centers participating (multicenter vs single center), total number of patients randomized, and the number of patients analyzed in each group. As for the patient and surgery characteristics, we will extract the following: age, sex, prior chronic use of opioids and dependence, preoperative pain, type of surgery and anesthesia, type of population (geriatric or not), follow-up period, and surgery setting . As for the intervention and comparator, we will extract the type, timing, and dose of the first gabapentinoid and comparator intake and the daily dosage, including the duration of treatment. For co-analgesia, we will include information about drugs, routes of administration, and regimen (regular vs. on request). Information concerning outcomes, such as postoperative acute (rest or dynamic) and chronic pain, cumulative ME administration, and length of stay in different hospital units , will be collected. Reported adverse events will be extracted, including dizziness, fall or ataxia, delirium, addiction or abuse, visual disturbance, respiratory failure, and PONV. In addition, we will extract information concerning study duration, conflict of interest, funding sources from pharmaceutical industry, and risk of bias items. When results are only presented on a diagram or a graph, data will be extracted using a web application (WebPlotDigitizer) .For every time point, pain measurement scores and standard deviation will be converted to a 100-point scale . OutcomeTwo independent reviewers (MV and XS) will evaluate the methodological quality of included trials using the Cochrane Collaboration’s tool for assessing risk of bias . This toI2 index [I2 greater than 50% indicative of significant heterogeneity. If deemed appropriate, we will conduct a meta-regression to analyze the effect of the cumulative dosage of gabapentinoids until 12 h after surgery using R software [R software [Data will be analyzed with Review Manager; version 5.3.5  using random effects models (Mantel-Haenszel for binary outcomes and inverse variance for continuous outcomes). We will represent pooled continuous data as weighted mean differences (WMD) with a 95% confidence interval and pooled dichotomous data as risk ratios (or odds ratio (OR) in the case of rare events if deemed appropriate). We will perform subgroup and sensitivity analyses to evaluate the robustness of our findings and potential sources of heterogeneity. We hypothesize that the following factors may explain heterogeneity: type of funding , type of surgery , type of follow-up (inpatient or ambulatory surgery), type of population , type of anesthesia , type of drug , the dosage regimen , low dose , or both and single or multiple intake), timing of the intervention , context of pain assessment , type of comparator , type of co-analgesia , and the overall risk of bias  , 39. We I2 index . We willsoftware . We willsoftware . To facisoftware . If apprsoftware , 43. We software .Gabapentinoids are widely used as an off-label treatment for the relief of chronic pain condition and are increasingly used for the management of postoperative acute pain, while the level of evidence supporting such usage is unclear . Our sysOur study will provide an accurate synthesis of the level of evidence for the perioperative use of gabapentinoids.Additional file 1:Search strategy for MEDLINE/Ovid. (DOCX 85 kb)