The purpose of the present study  was to evaluate the preemptive analgesic effects of pregabalin combined with celecoxib in total knee arthroplasty (TKA). n = 36), celecoxib group (n = 38), pregabalin group (n = 38), and combination group (n = 37). Each group was given the corresponding preemptive analgesia regimen at 12 and 2 hours before surgery. The pain score at rest and upon movement, cumulative dosage of sufentanil, knee range of motion (ROM), high-sensitivityC-reactive protein (hs-CRP) level, and adverse effects were evaluated after TKA to compare the effects of the preemptive analgesia regimens among the four groups.  From January 2019 to June 2021, we enrolled 149 patients who underwent TKA and divided them into four groups: the placebo group (P < 0.05). The cumulative dose of sufentanil within 48 hours after surgery was lowest in the combined group among the four groups (P < 0.05). Hs-CRP, ROM, and postoperative nausea and vomiting (PONV) were within 72 hours after surgery significantly improved in the combination group compared with those of the three other groups (P < 0.05).  The pain scores upon movement were significantly lower in the combination group than in the other three groups at 6, 12, 24, and 48 hours after surgery (ChiCTR2100041595. The preemptive analgesia regimen of pregabalin combined with celecoxib had positive effects on improving acute pain and reducing the cumulative dose of opioids after TKA. This trial is registered with  Total knee arthroplasty (TKA), a surgical method for the treatment of terminal stage knee osteoarthritis, can effectively relieve pain and restore knee function. However, patients experience moderate to severe pain after TKA. Acute pain after TKA can have a negative effect on enhanced recovery after surgery among patients . If acutThe mechanism of postoperative pain is complicated. In the past, it was believed that postoperative pain after TKA was mainly nociceptive pain caused by surgical trauma and tissue inflammation . Howeverγ-aminobutyric acid (GABA). Different from the mechanism of traditional analgesics, it has obvious anti-central and peripheral pain sensitization effects through inhibiting the voltage-dependent calcium channels of the peripheral and central nervous systems [The use of oral analgesics in advance is a convenient and effective method for preemptive analgesia after TKA. Celecoxib or other cyclooxygenase-2 (COX-2) inhibitors selectively inhibit the activity of COX-2, reduce prostaglandin production and inflammatory reactions, and achieve effective control of pain and anti-peripheral pain sensitization effects. In particular, it has a positive effect on reducing nociceptive pain mediated by inflammatory mechanisms after TKA , 12. Man systems . Therefo systems , 18. TheThe purpose of our study was to evaluate the effectiveness of pregabalin combined with celecoxib as TKA preemptive analgesia by compared the pain score, cumulative dosage of opioids, high-sensitivity C-reactive protein (hs-CRP) level, and adverse effects after TKA. We hypothesised that the effectiveness of pregabalin combined with celecoxib as TKA preemptive analgesia would lead to satisfactory clinical outcomes.http://www.chictr.org.cn . All patients signed written informed consent forms.The present study was a double-blind randomized clinical trial and was conducted in the affiliated hospital of our university. The study was approved by the ethics committee of the affiliated hospital of our university and conducted in accordance with the Declaration of Helsinki. In addition, the study was retrospectively registered at From January 2019 to June 2021, 201 patients who underwent TKA were subjected to a strict eligibility review. The inclusion criteria were as follows: patients who received elective, initial, and single TKA. The exclusion criteria were as follows: (1) patients with an American Society of Anesthesiologists (ASA) classification of grade 4 or higher, (2) patients with a history of liver and kidney insufficiency, severe cardiopulmonary disease, severe digestive tract disease, and mental illness, (3) patients with an allergy to celecoxib or pregabalin or to anesthetic drugs, (4) patients who had taken celecoxib or pregabalin within 2 weeks before surgery, and (5) patients with cognitive impairment. A total of 160 patients were finally included in the study.μg/kg + ondansetron 0.3 mg/mL + 0.9% sodium chloride injection, which were diluted to 100 mL. The first loading dose was 3 mL; there was no background dose. The additional dose of self-controlled analgesia was 1 mL each time, the lock-in time was 15 min, and the use of PCIA lasted for 48 hours. After the surgery, if the patients had a visual analog scale (VAS) score >4, 10 mg morphine was given as remedial analgesia, and none of the patients underwent a nerve block. All patients were managed with a standardized TKA accelerated rehabilitation program, and immediately after the operation, they were instructed to perform lower limb quadriceps muscle contraction exercises, lower limb ankle pump exercises, and active and passive knee flexion activities.Pregabalin and celecoxib are produced by Pfizer in the United States under the trade names Lyrica and Celebrex, respectively. Pregabalin, celecoxib, and the placebo were packaged in the same opaque packaging by the University Hospital Health Research Center pharmacy. The placebo capsule contained a mixture of 50% cellulose and 50% starch. An assistant from the Clinical Research Center used a random number table to divide the patients into four groups: the control group, celecoxib group, pregabalin group, and combination group. The patient group assignments were sealed in envelopes. Anesthesiologists who did not participate in the study opened the envelope 12 hours before the surgery, distributed drugs according to the patient group assignment, and distributed the same drugs again 2 hours before the surgery. The researchers involved did not know the patient group assignment during the surgery or data analysis. The medication program was as follows: placebo group: 200 mg + 150 mg placebo; pregabalin group: 150 mg pregabalin + 200 mg placebo; celecoxib group: 200 mg celecoxib + 150 mg placebo; and pregabalin combined with celecoxib group: 150 mg pregabalin + 200 mg celecoxib. Each group was given the same medication program again 2 hours before surgery. The patients were closely monitored for adverse effects after each administration of the medicine. All patients were given general anesthesia by senior anesthesiologists in our hospital. All operations were performed by two senior doctors with more than ten years of experience in TKA. Periarticular infiltration of the cocktail ingredient (0.5% ropivacaine + 10 mg/ml triamcinolone acetonide acetate + 0.1% epinephrine hydrochloride) was performed before closed the incision. Afterwards, the four groups of patients received patient-controlled intravenous analgesia (PCIA) immediately after the laryngeal mask was removed. The analgesic formula was sufentanil 2 The main observation indicators included the following:(1) VAS pain score at rest and upon movement at 6, 12, 24, and 48 hours after the surgery ; (2) cumulative dose of opioids within 48 hours ; (3) the hs-CRP level before and after the surgery; (4) time of first successful straight leg elevation: the standard is that the patient can maintain a flexed ankle joint and straight leg raise at least 40 cm above the bed for more than 4 s; (5) maximum knee flexion range of motion (ROM) at 24, 48, and 72 hours after surgery; (6) time to first remedial analgesia after surgery; and (7) complications including postoperative nausea and vomiting (PONV), dizziness, gastrointestinal hemorrhage, urinary retention, deep vein thrombosis (DVT), and severity of sedation.P < 0.05 indicated that the difference was statistically significant.Power analysis was performed based on the data from a previous study  to calcuA total of 160 patients were enrolled in the study, 7 patients discontinued PCIA because of severe vomiting reaction to sufentanil. 2 patients asked to withdraw from the study and 2 patients were suspended surgery. Consequently, 149 patients were included in the final data analysis. The CONSORT study participant flow diagram is shown in P > 0.05)  .P < 0.05). The pain scores at rest in the combination group were significantly lower than those in the celecoxib group at 6 hours after surgery (P=0.018 < 0.05) (P < 0.05)  = 37.88, P < 0.001). Then, a simple effects model was used for further analysis. In terms of a time effect, we observed that the pain score on movement in the combined group showed a significantly continuous downward trend over time within 48 hours after surgery (P < 0.05) (µg) was significantly lower than those of the other three groups within 48 hours after surgery (P < 0.05) (P < 0.05).As shown in  < 0.05) . The pai < 0.05) . There w < 0.05) . The cum < 0.05) . The firP=0.386). The hs-CRP level was significantly lower in the combination group than in the other three groups at 24, 48, and 72 hours after surgery (P < 0.05). The hs-CRP level was significantly lower in the celecoxib group than that in the pregabalin and placebo groups at 24, 48, and 72 hours after surgery (P < 0.05) (P < 0.05) (P < 0.05). As shown in P < 0.05).As shown in  < 0.05) . ROM inc < 0.05) . The timX), and the cumulative dose of sufentanil within 48 hours was the dependent variable (Y). The regression equation   was the independent variable (< 0.001)  suggestePerioperative pain management is key to the smooth implementation of enhanced recovery after surgery (ERAS), which has rapidly become a popular concept in the field of orthopedics. Although the combined application of various postoperative analgesia methods can improve the postoperative acute pain of TKA patients, many still suffer from moderate or even severe pain , 20.Preemptive analgesia is an important part of multimodal analgesia, and its value is increasingly recognized by clinicians and researchers. Some studies have found that preemptive analgesia can further improve postoperative pain in TKA patients –10. HoweIn the present study, we observed that the combination group had better improvement in pain scores at rest and upon movement than the other three groups. The pain scores at rest in the combined group were always low level within 48 hours, and unlike the placebo group, there were no large fluctuations in pain scores, which indicated that the analgesic effect of the combination regimen was stable and relatively durable. However, the pain upon movement was more significant than that at rest because all of the patients need to exercise as soon as possible after TKA to enhance recovery. In the study of Lee et al. , patientCurrently, analgesia after TKA mainly involves a variety of opioids, such as sufentanil, tramadol, and morphine. Opioids mainly act on opioid receptors in the pain center of the brain to inhibit the generation and amplification of pain signals. However, opioids have significant side effects, such as nausea and vomiting, drug dependence, urinary retention, excessive sedation, and respiratory depression. The majority of TKA patients are elderly patients, and the incidence of opioid side effects is significantly higher in elderly patients than in young and middle-aged patients . One of The key core of preemptive analgesia is to reduce the degree of peripheral and central pain sensitization and to improve the pain threshold of patients in advance . Lower lOur study has some limitations. First, our research was limited to within 72 hours after surgery, so we cannot be sure whether control of acute postoperative pain can promote long-term knee function recovery and reduce the possibility of long-term chronic pain. Second, we did not accurately estimate sample size, which may affect the efficacy of the present study. Third, according to the relevant study , the minLast, in terms of postoperative complications, our sample size was too small to comprehensively and objectively evaluate the safety of analgesia programs.The preemptive analgesia regimen of pregabalin combined with celecoxib had positive effects on improving acute pain and reducing the cumulative dose of opioids after TKA.


Postoperative pain is one of the most common postoperative complications, resulting in significant burdens and adverse outcomes among patients, notably the frailest ones. Predicting the likelihood of intense postoperative pain can help optimize a patient’s recovery. The aims of this study were to build a prognostic model of pain persistence in elderly and senile patients in the late postoperative period, based on clinical and laboratory parameters of the early postoperative period, and to evaluate the potential for the model’s application. The study included 201 male and female patients who had undergone surgery of any type from September 2019 to August 2020. The patients were divided into three groups: senile patients, elderly patients, and young patients (control group). All of the examined patients were measured for fasting cortisol on the mornings of the first and seventh days following surgery. A statistically significant increase in the probability of pain persistence in the late postoperative period with the increasing age of the patient was found. Age, pain severity scores on the seventh day after surgery, and cortisol concentration in the blood on the first day after surgery, are of prognostic value for the risk of persistence of postoperative-pain syndrome. Postoperative pain is one of the most common complaints in surgical practice; hence, its management is of great clinical importance. Evidence suggests that between 35% and 70% of patients who have undergone elective and emergency surgery suffer from postoperative pain. In one of the largest studies of patients in surgical departments in the UK, it was found that 10.9 percent of patients experienced high-intensity postoperative pain, while 29.7 percent of patients experienced medium-intensity pain [According to the International Association for the Study of Pain (IASP), pain is an unpleasant sensation and an emotional experience associated with actual or potential tissue damage or the time described by the patient for such damage . DespiteThe etiology of pain in old and oldest-old patients, who constitute a high-risk demographic for postoperative complications, is complex. Age- and frailty-related alterations in neurohumoral regulation and the emotional burden of nociceptive impulses have a compounding effect on pain-related distress among this group of patients. In particular, the pineal gland undergoes age-related calcification, which causes morpho-functional changes in daily activity and sleep quality ; olfactoInadequate management of acute postoperative pain is associated with increased morbidity, functional impairment, reduced quality of life, and increased health care costs. In addition, the existence and intensity of acute pain enable us to predict the likelihood of its chronicity . This riThe aims of this study were to build a prognostic model of pain persistence in old and oldest-old patients in the late postoperative period, based on clinical and laboratory parameters of the early postoperative period, and to evaluate the potential for the model’s application.The study was conducted in the 3rd Poltava City Hospital from September 2019 to August 2020. The criteria for inclusion in the study were patients aged over 18 years, patients who underwent elective surgery, and patient complaints of postoperative pain of any intensity. Patients younger than 18 years, patients who experienced open surgery, patients receiving chronic pain medication, expectant mothers, patients with delirium in the postoperative period, patients with hormonal and mental disorders in the stages of sub- or decompensation, and patients who underwent neurosurgical operations were excluded from the study, because of the potential impact of the operation on the pain sensation of such patients. A total of 317 patients were evaluated, 116 of whom were excluded from the analysis due to the presence of exclusion criteria (n = 83), the incompleteness of the entire research protocol (n = 21), or the patient’s own request (n = 12). The study included 201 male and female patients who had undergone laparoscopic (n = 164) or robotic (n = 37) surgery. All patients underwent control of perioperative pain in accordance with pertinent guidelines on the control of perioperative pain [The examined patients were divided into 3 groups according to age : old patTo assess the presence and severity of pain, measurements were performed on a 100-point visual analog scale (VAS) on the first and seventh days following surgery . This scale is based on a 10 cm segment with 100 divisions, where 0 represents no pain and 100 represents unbearable pain. The scale has been previously validated for clinical research in a similar context . The McGAll examined patients were measured for fasting cortisol in the morning on the first and seventh days. The blood sampling procedure was performed according to the general requirements for medical and biological tests at Poltava State Medical University, Ukraine . A nurse2-Pearson was used to compare qualitative variables. Quantitative data were presented according to the distribution, which was analyzed according to the Kolmogorov–Smirnov criterion. Data that corresponded to the normal distribution were presented as mean (M) and standard error (m) and compared using one-way analysis of variance ANOVA, with a posteriori comparison according to the Scheffe test. To build a prognostic model, we carried out a multivariate binary logistic analysis with the calculation of the coefficients of the prognostic equation and the determination of the odds ratio and a 95% confidence interval for significant factors. Quality assessment of the prognostic model was performed by ROC analysis with the choice of maximum sensitivity and specificity. The choice of the optimal limit value of the test was performed by the method of calculation of the Yoden Index. For all measurements, the critical value was p < 0.05, at which the results were considered statistically significant.Statistical analysis was performed using IBM SPSS Statistics 26.0 . Qualitative variables were presented in the form of absolute numbers and percentages with relative deviation. ΧAll patients included in the study provided informed consent in the preoperative period. The study was approved by the Bioethics Committee of Poltava State Medical University and conducted in accordance with the basic provisions of the “Ethical Principles for Medical Research Involving Human Subjects”, approved by the Declaration of Helsinki (1964–2013) and following the recommendations of good clinical practice (ICH GCP) (1996) and orders of the Ministry of Health of Ukraine No. 690, dated 23 September 2009, No. 944, dated 14 December 2009, and No. 616, dated 03 August 2012.On the first day following surgery, 11 patients in the first group reported mild pain (13.4 ± 0.68%), 30 patients reported moderate pain (36.6 ± 0.98%), 23 patients reported severe pain , 15 patients reported extremely severe pain (18.3 ± 0.69%), and three patients reported unbearable pain (3.7 ± 0.11%). Among group 2 patients, there were no patients who described the pain as mild or unbearable. Moderate pain was detected in eight patients of group 2 (38.9 ± 0.34%), severe pain was detected in nine patients of group 2 (49.2 ± 0.85%), and very severe pain was detected in four patients of group 2 (19.0 ± 0.08%). Among patients in the control group, 13 (13.3 ± 0.17%) did not indicate the intensity of pain, 34 (34.7 ± 0.44%) reported mild pain, 29 (29.6 ± 0.39%) reported moderate pain, 13 reported severe pain (13.3 ± 0.87%), eight reported very severe pain (8.2 ± 0.09%), and one reported unbearable pain (1.0 ± 0.02%). Seven days after surgery, in group 1, mild pain was noted in 16 patients (19.5 ± 0.65%), moderate pain was noted in 21 patients (25.6 ± 0.53%), severe pain was noted in 19 patients , and very severe pain was noted in 14 patients (17.1 ± 0.43%). In group 2, mild pain was noted in one patient (4.8 ± 0.16%), moderate pain was noted in 3 patients (14.3 ± 0.28%), severe pain was noted in 13 patients (61.9 ± 0.71%), and very severe pain was noted in two patients (9.5 ± 0.13%). In the control group, mild pain was noted in 24 patients (24.5 ± 0.59%), moderate pain was noted in 25 patients (25.5 ± 0.93%), severe pain was noted in 14 patients (14.3 ± 0.45%), and very severe pain was noted in seven patients (7.1 ± 0.14) %). On the seventh day, the subjective perception of postoperative pain was detailed according to the MPQ. According to the MPQ evaluation scale, patients in groups 1 and 2 indicated moderate postoperative pain , while in the control group a slight degree of pain intensity was determined (1.71 ± 0.12 points). The distribution of postoperative pain levels by the evaluative component of the McGill scale were analyzed according to the groups .2 = 43.49, p < 0.001) and on the seventh day .It was found that more intense pain is characteristic for older people in the early postoperative period on the first day (χp < 0.001) and between group 2 and the control group (p < 0.001). In addition, the evaluative assessment of old patients did not differ in a statistically significant way from that of oldest-old patients (p = 0.772). Significant differences were found between group 1 and the control group . In group 1, the RPI on the sensory scale was higher than that of the control group (p < 0.001) and lower than that of group 2 (p = 0.045), while the value in group 2 was higher than that of the control group (p < 0.001). The INSD on the sensory scale in the control group was lower than that of group 1 (p < 0.001) and group 2 (p < 0.001), and the INSD was lower in group 1 than in group 2 (p < 0.001).Both parameters of the sensory scale showed statistically significant differences among the groups . In the control group, this indicator was lower than it was in group 1 (p < 0.001) and group 2 (p < 0.001). However, no statistically significant difference was found between the old and oldest-old groups (p = 0.968). The INSD on the affective scale in group 1 was at the level of 6.40 ± 0.44 points; in group 2, it was 11.52 ± 1.55 points; in the control group, it was 6.23 ± 0.42 points. The indicators had statistically significant differences among the groups . In particular, in group 2, the INSD on the affective scale was higher than it was in group 1 (p < 0.001) and the control group (p < 0.001). However, no statistically significant difference was found between group 2 and the control group (p = 0.892).According to the affective scale, the RPI in group 1 was 5.32 ± 0.39 points; in group 2, it was 4.91 ± 0.73 points; in the control group, it was 1.99 ± 0.14 points. The differences among the groups were statistically significant . In addition, in patients in the control group, this figure was significantly lower (p < 0.001), at 589.99 ± 10.27 nmol/L. After 7 days in group 1, the level of cortisol decreased to 536.46 ± 3.82 nmol/L; in group 2, it decreased to 521.37 ± 9.58 nmol/L; in the control group, it reduced to 531.39 ± 3.65 nmol/L. These decreases were not statistically different (p = 0.223)  .2 = 31.07, p < 0.001).On the 14th day after surgery in the late postoperative period, 67 cases of postoperative pain were identified, of which 34 (41.5%) were in group 1, 16 (76.2%) were in group 2, and 17 (17.3%) were in the control group. A statistically significant increase in the probability of pain persistence in the late postoperative period with the increasing age of the patient was found  for each year of higher age, 1.26 times  for each point on a 100-point VAS scale on the seventh day, 11.37 times  for each point on the evaluation MPQ scale, and 2.36 times  for each nmol/l of cortisol concentration on the first day after surgery.We determined that age, the score on the VAS scale, the score on the MPQ evaluation scale on the seventh day, and the cortisol concentration in the blood on the first day after surgery are of prognostic value for the risk of persistence of postoperative-pain syndrome. The chance of persistence of postoperative pain increases 1.08 times :X1—age, years;X2—VAS scale on the seventh day, in points;X3—evaluation MPQ scale, in points;X4—concentration of cortisol in blood on the first day, in nmol/liter.Classification characteristics of the constructed model for predicting the risk of persistence of postoperative pain are presented in -the probability of a correctly predicted positive result (sensitivity) when using this model—87.1% (95% CI 82.9–91.3%);-the probability of a correctly predicted negative result (specificity)—95.4% (95% CI 93.7–97.1%);-the predictability of a positive test result—91.0% (95% CI 85.9–96.1%).-the predictability of a negative test result—93.3% (95% CI 86.9–99.7%).The accuracy of the constructed prognostic model was evaluated according to the data of the training sample and was 92.5% (95% CI 88.2–96.8%). Point and interval estimates of the efficiency of the regression model were calculated according to the matrix of classifications and were:To determine the adequacy of the constructed model, we analyzed the curve of the operational characteristics, which corresponded to our regression equation. See p < 0.001) and exceeded 0.5, which was evidence of the adequacy of the constructed model  was statistically significant  reported a mild, and potentially not clinically significant, increase in postoperative pain as a function of increasing age, based on a cohort of 11,510 patients from 26 countries . Younger21 reportTo date, various models for assessing the course of the postoperative period have been proposed and used ,17. Our Our study is subject to a number of limitations. Due to limited funds, the sample size and the follow-up period could not be increased further than reported. Collecting relevant data from multiple institutions at national or international levels can indicate whether our results are repeatable. Additional variables related to the type of surgical interventions—including the duration of anesthesia, the pharmacological groups of drugs, and patients’ mental status, which may impact on perceived pain severity, have not been analyzed. Presently, we focused on the evaluation of postoperative-pain differences among three specific age and morbidity groups. Based on our findings, it is possible to conduct further subgroup analysis and to unravel the predictors of pain intensity among old and oldest-old patients.In this article, we were able to predict the persistence of pain in the late postoperative period by identifying clinical, psychophysiological, and laboratory characteristics of the early postoperative period. Age, pain severity on the VAS scale and the MPQ evaluation scale on the seventh day, and cortisol concentration in the blood on the first day are the four characteristics we used to build a binary logistic regression model to predict the risk of pain-syndrome persistence in the late postoperative period.


This study aimed to evaluate the association of the variables age, gender, arch position, tooth length, root canal amplitude, and periapical lesion size with the occurrence of postoperative signs and symptoms  and the use of postoperative analgesics following root canal treatment with foraminal enlargement in single-rooted teeth with apical periodontitis. This prospective longitudinal study included 105 patients requiring root canal treatment of maxillary or mandibular single-rooted teeth with periapical lesion. After root canal treatment in a single session, pain intensity and tenderness were recorded daily for 7 days and on days 14 and 30. Edema was evaluated by two independent evaluators within 48 h, 72 h, and 7 days after treatment. Ordinal and logistic regressions were performed (p < 0.05). Female gender , mandibular teeth , medium root canal amplitude , and edema  were associated with increased postoperative pain and tenderness, while the use of analgesics  and time in days  were associated with a decrease in these signs and symptoms. Edema was considered a risk factor for analgesic requirement . Factors such as gender, arch position, and root canal amplitude were associated with postoperative signs and symptoms. The use of analgesics was more required in edema and was associated with decreased pain. The null hypothesis was that there is no relationship between these factors and the occurrence of postoperative signs and symptoms and analgesic requirements.This prospective longitudinal study was approved by the local ethics committee (no. 2.353.996), and was reported following the Guidelines for reporting non-randomized studies The study population comprised patients over 18 years of age who presented to the Faculty of Dentistry of the Fluminense Federal University/Health Institute of Nova Friburgo, Rio de Janeiro, Brazil, for the evaluation and management of deep carious lesions, between March 2019 and February 2020.The sample size was determined using the OpenEpi calculator (https://www.openepi.com/Menu/OE_Menu.htm). The sample was calculated by estimating the prevalence of severe postoperative pain on the first day after root canal treatment with foraminal enlargement of necrotic teeth, which was reported to be 34% Patients included in the study required at least one root canal treatment on the maxillary or mandibular single-rooted teeth with periapical lesion without preoperative pain or edema. The exclusion criteria for the study were as follows: 1) patients with systemic disorders; 2) allergy to ibuprofen; 3) used antibiotics in the last 30 days A single specialist (E.A.B.S), with 35 years of experience, performed the clinical procedures in a single session using a standardized protocol. Digital periapical radiography  was performed in a standardized form to aid in diagnosis and follow-up. Dental biofilms were removed by professional oral prophylaxis, and the patients were instructed to rinse with 15 mL of 0.12% chlorhexidine gluconate for 1 min . The diagnosis of pulp necrosis was determined by sensitivity tests to cold with Endo Ice  and hot with a heated gutta-percha stick . Patients were anesthetized with 2% lidocaine with 1:100,000 epinephrine , and endodontic access was performed with a sterile diamond bur , at high speed. Rubber dam was placed and disinfected with 2.5% NaOCl . The working length (WL) was measured with a size 15 K-file (Dentsply Sirona), and the patency was maintained with a size 10 K-file (Dentsply Sirona). Odontometry determination was performed using the apical locator RomiApex A-15 , and WL was established at the “00” mark.Based on the initial radiographs and the anatomical diameter of the root canal determined by initial exploration, up to the WL, with sizes 10, 15, 20, 25, and 30 K-files (Dentsply Sirona), under constant irrigation, 40 or 50 Reciproc files , coupled to the Silver engine , were selected for instrumentation. In cases where a size 30 K-file did not move passively to the WL, R40 was selected, and these cases were classified as medium. In cases where a size 30 K-file passed passively to the WL, R50 was selected, and these cases were classified as large, according to the manufacturer's protocol. The instruments were introduced with linear back-and-forth movements with an amplitude of 2, using a 30-G irrigation needle  up to 2 mm short of the final WL Sterile absorbent paper cones from the Reciproc System (VDW) were used inside the root canal before obturation, which was performed with the gutta-percha cones of the system (VDW), R40 or R50, and MTA Fillapex , using lateral condensation. Finally, the tooth was restored with a definitive restorative material. The occlusion was checked and adjusted.2).Data on the following variables were collected: age, gender, arch position (maxilla or mandible), tooth length (mm), root canal amplitude (teeth instrumented with R40-medium or R50-large), and periapical lesion size .The amplitude of the root canals was determined by the taper of the selected Reciproc file, which was classified, according to the manufacturer, as large and medium when the Reciproc 50 and 40 files, respectively, were used for instrumentation of the root canals.2.The size of the periapical lesion was determined using ImageJ/Fiji 1.46 (http://imagej.nih.gov/ij/) software. The initial standardized radiography of each case was inserted into the software, and through the delimitation of the lesion by a single operator (L.S.G) and specific tools, the lesion area was determined in mm,,,,,,,The outcome variables were postoperative pain, tenderness, and edema. The use of analgesics after root canal treatment with foraminal enlargement in single-rooted teeth with periapical lesion was also noted. The analyses of postoperative pain and tenderness were performed using the visual analogue scale (VAS), which was delivered to all patients to record the pain assessment daily for 7 days and on days 14 and 30 after root canal treatment. The VAS consisted of a horizontal ruler with two endpoints (0 indicating no pain and 10 indicating severe pain). The distance from 0 to the mark made by each patient was measured with a ruler, and the resulting quantitative values were used in the statistical analysis. Pain levels were classified as no pain (0), mild Based on the criteria of Morse et al. Mild: there is no distortion of the face but slight swelling of the gingiva, cheeks, or chin.Moderate: there is a superficial distortion of the cheek or chin.Severe: there is a severe distortion of the part involved.The data were analyzed using the Statistical Package for Social Science software . The level of significance was set at 5% (p < 0.05).The normality of the continuous predictor variables was evaluated using the Kolmogorov Smirnov test, as none of the variables showed a normal distribution (p<0.05). The Mann-Whitney U-test and Spearman’s rank correlation were applied to assess the association between the predictor variables and postoperative pain and tenderness daily, for 7 days, and on days 14 and 30 after root canal treatment. These predictor variables were also assessed for edema and use of analgesics using the Chi-square, Fisher’s exact and Mann-Whitney U tests. Multivariate Ordinal Regression using the Generalized Estimating Equation model (GEE) was performed to evaluate the association between VAS values and predictor variables adjusted by analgesic use. All predictor variables were added in the regression models.A total of 105 patients were included in this study. One patient was lost to follow-up for postoperative pain and tenderness . The meaThe incidences of postoperative pain and tenderness were 38.46% (n = 40) and 42.31% (n = 44), respectively. Nineteen (18.27%) patients had mild postoperative pain, 10 (9.62%) had moderate pain, and 11 (10.58%) had severe pain. Regarding tenderness, 24 (23.08%) presented with mild pain, nine (8.66%) presented moderate pain, and 11 (10.58%) presented severe pain.Edema and the use of analgesics were also evaluated in multivariate analysis by Logistic Regression, as shown in ,Postoperative signs and symptoms are undesirable for both patients and clinicians in daily endodontic practice ,,,,Root canal treatment with foraminal enlargement and reciprocating instrumentation in a single session was performed in 105 patients. We included only asymptomatic patients because the inclusion of teeth with preoperative pain and edema could influence the results ,,,, The presence of microorganisms in the apical portion of the canal and even within the lesion itself has led to the proposal of cleaning, debridement, and enlargement of the apical foramen during root canal instrumentation ,,,,,,,,,,,,1,,,The relationship between risk factors and postoperative signs and symptoms has been studied by several authors .In this study, the patients’ age did not show significant effects on the occurrence of postoperative signs and symptoms. These findings aligned with several studies 14,16.Regarding the arch position, the mandibular teeth were responsible for greater postoperative pain and tenderness, which can be explained mainly because of its thick mandibular cortical plaque and the consequent lack of space for pressure dissipation due to the accumulation of inflammatory exudates ,We also observed a significant difference in the amplitude of the root canal considered as medium. This significant difference may be related to the extrusion of debris during the cleaning and shaping of the root canals. In our study, single-rooted teeth with periapical lesion were subjected to root canal treatment with reciprocating instrumentation and foraminal enlargement, and even with all well-established and evidence-based protocols ,However, it is worth pointing out that several studies ,,,2 and did not show statistically significant results.It is also known that a higher incidence of postoperative signs and symptoms occurs in teeth without periapical lesion or with very small lesions, which can be attributed mainly to the lack of space for pressure release when periradicular bone resorption is absent ,,Another risk factor identified in our study as a potentially important prognostic factor for postoperative symptoms was gender, in agreement with the results obtained by the retrospective study conducted by Torabinejad et al. Finally, the use of analgesics was directly proportional to the occurrence of postoperative signs and symptoms, thus, edema was considered a risk factor for the analgesic requirement. However, the use of postoperative analgesics and time in days was associated with decreased postoperative pain, which was already expected, as the intensity of the pain decreased substantially in the first few days. It is worth mentioning that patients were only medicated when requested, an essential factor in avoiding erroneous estimates in this study.,.Although our study has a few methodological biases, it has some limitations. First, the VAS did not indicate the source of postoperative pain and tenderness. The perception of pain is subjective and strongly dependent on the patient's cultural, individual, and economic context. For this reason, the design of the questionnaire is critical and must ensure that it will be fully understood by patients and easily interpreted by researchers Therefore, it is necessary to carry out other studies with adequate sample sizes and well-developed methodologies to confirm or refute the various critical factors to the postoperative signs and symptoms found in this study.Female gender, mandibular teeth, and medium root canal amplitude could be factors associated with postoperative signs and symptoms in root canal treatment with foraminal enlargement in single-rooted teeth with apical periodontitis. The use of analgesics was most required in patients who presented edema, and it was associated with decreased pain over time.


Orofacial pain and tensional cephalea were symptoms commonly reported in COVID-19 patients, even after recovery, and were considered chronic pain in these cases. The aim of this research is to evaluate the effect of the application of photobiomodulation with red and infrared lasers applied locally and systemically.t test, Kruskal–Wallis, or Wilcoxon, according to data distribution. α = 0.05 will be considered as the level of statistical significance.For this purpose, individuals who have been diagnosed with COVID-19 and have had a tension headache and/or orofacial pain for more than 3 months will be selected by convenience. The participants will be divided into two different groups: G1-photobiomodulation with red and infrared laser with local application on the pain points  and G2-photobiomodulation with red laser with transcutaneous application on the radial artery . All participants will be treated for a period of 4 weeks, with 8 application sessions. The effects will be measured by means of blood lactate level, Brief Pain Inventory, Visual Analog Scale (VAS), and Cephalea Impact Test. The data will be collected weekly before and after the treatment, and the following tests will be applied: Analysis of variance (ANOVA), Tukey paired ClinicalTrials.gov database with the number NCT05430776.This study was approved by the Research Projects Committee of the Nove de Julho University . Results will be disseminated through peer-reviewed journals and events for the scientific and clinical community, and the general public. It is registered in the  This study is an assessment for treatment for health impacts of the pandemic. This is a pragmatic study. Lasertherapy can be a non- invasive proposal for the treatment of pain resulting from COVID-19. There is not enough information in the literature on the relationship between laser therapy and post-covid-19 pain-related sequelae.,2Orofacial pain is defined as pain associated with tissues  of the oral cavity and face. Often, this pain can be referred to the head and/or neck region or even associated with cervicalgia, primary headaches, and rheumatic diseases.,4Cephalea refers to any referred pain in the cephalic segment and is a very common manifestation. During life, the prevalence of cephalea is higher than 90%, representing the third most common occurrence (10.3%) in neurology outpatient clinics. Cephalea is considered a public health problem, as they are debilitating disorders that sometimes make routine actions impossible, which causes a great personal and social impact. This kind of pain is described as a pressure with mild to moderate intensity, bilateral.According to the International Classification of Cephalea, there are five predominant types of primary Cephalea, the most common being tension-type cephalea (TTH).TTH is the most prevalent type worldwide, and the stiffness in the myofascial tissue in the cervical and cranial region strongly connects with the frequency and intensity of the discomfort. Genetic, emotional, and peripheral factors, such as nociception and central factors , are noted as etiological for orofacial pain.,8In addition to tension headache, temporomandibular disorders (TMD) are related to orofacial pain with signs and symptoms that include joint noises, limitations in range of motion or deviations during mandibular function, and temporomandibular joint pain.In 2020, the world was surprised by the pandemic of COVID-19, a disease caused by the coronavirus (SARS-CoV-2). The disease affected millions of people, causing many deaths. The clinical course of this new infection is characterized by respiratory symptoms and complications, however, cephalea is one of the signs frequently reported by COVID-19 patients.The cephalea attributed to the current viral infection is known as migraine or TTH, according to the 3rd edition of the International Classification of Headaches.It is estimated that with the pandemic COVID-19 there has been a 5-fold increase in the incidence of cephalea, and the most frequent pattern is bilateral. Other conditions were also evaluated the duration, frequency, course of the pain, and the relationship with a possible post-COVID-19 syndrome, as the disease has potential medium and long-term consequences.,13The worsening of the psycho-emotional state during the pandemic contributed not only to the increased incidence of cephalea but also to TMD-related pain. However, in addition to psychosocial factors, the involvement of facial sensory innervation such as olfaction and taste. Although independent structures, there is an interrelationship between the olfactory nerve and the trigeminal nerve, contributing to the development and prolongation of orofacial pain.The importance of psychosocial factors in the development and maintenance of TMD is well established, and these factors have become more threatening to orofacial pain during the pandemic.The recommended treatment for orofacial pain, as well as for cephalea, in general, aims at reducing the pain symptom and recovering the function. Pain control is often accomplished with the prescription of analgesics, anti-inflammatories, and other types of auxiliary drugs. However, in post-COVID-19 patients, pharmacological treatment may result in drug interactions resulting from the treatment for the viral infection. Considering this, the non-pharmacological auxiliary options that have the potential to contribute to pain relief can be considered.One of the auxiliary treatment options for analgesia in TTH and TMD orofacial pain is photobiomodulation, that is, the use of a low-intensity laser or even light-emitting diode.–20Low-intensity laser therapy (LILT) is being used frequently as a therapeutic procedure in a variety of medical situations, such as edema and inflammation control, chronic joint disorders, pain, and wound healing, among others.–24 LILTs have demonstrated the ability to aid in the symptomatic treatment of pain, providing a considerable degree of comfort to patients right after their application. One of the main advantages of LILT is that it is a noninvasive, low-cost pain relief therapy. The use of laser therapy in patients with facial pain showed pain relief within minutes after its application, providing a significant well-being state. It is an auxiliary treatment for pain relief due to the analgesic action of the laser that allows the patient to resume their activities, providing more comfort and a better quality of life.,22,24–26Chronic cephalea and cephalea associated with TMD have benefited from photobiomodulation for pain control. Therapeutic effects of LILT in TMD and headaches include an inflammatory modulator and analgesic effects.Considering the auxiliary potential effect of photobiomodulation in controlling persistent TTH and TMD-related pain in patients who have been diagnosed with COVID-19, and are recovered from the viral infection, we intend to conduct a clinical trial comparing two modalities of therapeutic laser application: local application and transcutaneous application in the radial artery.One of the main advantages of auxiliary techniques in pain control is the decrease of the use of drugs for analgesia, avoiding side effects and tolerance caused by them, and promoting an improvement in the individual’s quality of life.This is a pragmatic, randomized, parallel, single-blind clinical trial. The design follows the international recommendations for randomized clinical trials that are displayed in the SPIRIT Statement .The research follows the regulatory norms established for human subjects research by the Research Ethics Committee of the Nove de Julho University with approval under number 4.673.963 that will periodically monitor the conduct of the study through semiannual reports. This is a low-risk study and symptom relief assessment does not require DMC. The participants will sign the free consent form after clarification, according to resolution 466/12 of the National Health Council. The recruitment procedures, eligibility assessment, and treatment will be carried out at UNINOVE’s Integrated Health Outpatient Clinics.The selected subject will be individuals from the ages of 18 to 65 years, of both sexes, who have been diagnosed with COVID-19, confirmed by RT-PCR for SARS-CoV-2 already recovered at least 30 days from the infection, and present with orofacial pain will be selected. with a margin of error of 5%, reliability of 95%, and power of 80%, we intend to recruit, at least, 40 participants.Since this is a new scenario in health care and the information on the participants’ conditions is very recent, we chose a convenience sampling design. Considering a prevalence of persistent orofacial pain in infected participants of 11%,Participants will be invited to participate in the selection criteria that will follow the routine anamnesis and diagnosis of the International Classification of Headache and orofacial pain questionnaire.-Individuals of both sexes, between the ages of 19 and 65, complaining of persistent orofacial pain or functional-type cephalea, for more than 3 months.-Individuals diagnosed with COVID-19, confirmed by RT-PCR for SARS-CoV-2 already recovered, at least 30 days after infection.-Individuals with diagnoses of neuropathies and headaches other than tension-type headache-Physical or intellectual incapacity to answer the survey questionnaires; illiterate; diabetics, pacemakers, and pregnant women.-Individuals who report photosensitivity to laser.Participants who report any discomfort during the protocols, who present sensitivity to the laser application, or who do not attend more than two appointments in a row will be discontinued and the data will be computed for further analysis.Sociodemographic information will be collected, such as age, self-reported skin color, education, occupation, weight, height, and practice of physical activity. Besides the sociodemographic information, clinical information will be collected, such as the history of systemic diseases and personal and family history of health problems, treatments performed previously and at the time of the survey, and medications used.The Brief Pain Inventory (BPI) is a multidimensional instrument that uses a 0 to 10 scale to grade the following items: intensity, interference of pain in the participant’s ability to walk, daily activities, work, social activities, mood, and sleep. The pain rated by the participant is that experienced at the time of the questionnaire and the most intense, least intense, and average pain of the last 24 hours. The Brief Pain Inventory scale will be applied weekly.Visual Analog Scale for pain: one-dimensional instrument for pain intensity assessment. It is a line with the ends numbered from 0 to 10. At one end of the line is marked “no pain” and at the other end “worst pain imaginable.” The participant is then asked to evaluate and mark on the line the pain present at that moment. The Visual Analog Scale will be applied at the beginning and the end of each session.Headache Impact Test (HIT-6) – To evaluate the impact of the protocols used in the treatment of headache on the participants’ quality of life, the Headache Impact Test known as HIT-6 applied at the four moments of the participant’s evaluation, according to the study protocol. It is an easy-to-apply test, reliable, and validated for the Brazilian reality.The test consists of six questions, covering the domains of pain, ability to perform usual activities, social functioning, energy/fatigue, cognition, and emotional stress. Scores are calculated by assigning a value of 6 points when the answer is “never,” 8 points for “rarely,” points for “sometimes,” points for “very often” and 3 points when the answer is “always.” The score ranges from 36 to 78. If the score is <49 points, they suggest that the headache has little or no impact on the participant’s quality of life. If the score is 50 to 55 points, it means that there may be an impact on the daily activities, but the individual is still able to perform the activities normally. Scores between 56 to 59 points constitute substantial impact, that is, there is difficulty in performing simple daily activities due to the pain. Scores >60 points imply a very intense impact on quality of life, leading to the inability to perform daily activities. The HIT-6 test will be applied at the beginning and the end of the treatment.For blood collection, a disposable and sterile lancet will be used. A small prick will be made on the right earlobe, and the collected blood (25 µL) will be deposited on a reactive tape to be analyzed in a portable lactometer . The lactate level will be collected once a week, before and after the application of the protocol. The lactate level is related to muscle activity and may help in the understanding of the effect of photobiomodulation in this research.The need for medication changes or the introduction of new drugs other than the usual ones will also be collected by means of a medication recall.The treatment will be carried out in 8 weeks (2 sessions per week) with an average duration of 60 minutes per session. At the end of the 8-week treatment, a new evaluation will be performed after 1 month of follow-up.After selection, the participants will be randomized into two groups: (G1) photobiomodulation with red and infrared laser with local application on pain points and (G2) photobiomodulation with red laser with transcutaneous application in the radial artery.www.randon.org. The sequence will be kept in a sealed opaque envelope. Only one researcher will have access to the sequencing.The draw for allocation to the groups will be carried out by means of generating number sequences on the electronic platform After allocation, the participants will answer the evaluation scales and the blood will be collected for analysis of the initial lactate level Fig. .The participants will be positioned on a clinical chair or stretcher for the application of photobiomodulation at the Universidade Nove de Julho dental clinic. The interventions will be performed by trained professionals.G1 will receive the application of photobiomodulation with the device The Ecco Reability  containing its infrared wavelength of 808 ± 10 nm and red 660 ± 10 nm concomitant and power 100 mW, properly calibrated and energy of 6 J per point (60 seconds) in 8 points, 2 sessions per week in 8 points on the face and neck. The points will be those referred to by the participant as pain or trigger points located during the clinical examination. G2 will receive the application of photobiomodulation with the device The Ecco Reability (Eccofibras) containing its red wavelength 660 ± 10 nm concomitant and power of 100 mW, with an application time of 30 minutes  and attached to the wrist with a specific wristband. There will be 8 transcutaneous applications, 2 sessions per week of 30 minutes each session.Any changes made to the protocol will be communicated to the participants using the media of Universidade Nove de Julho and the academic community involved through attachments in the original project.t test will be used. If the hypothesis of normality is rejected, the Kruskal–Wallis test will be used followed by Student’s test, and for comparison in the different study periods, the Wilcoxon test will be used. We will take α = 0.05 as the level of statistical significance.The data will be presented descriptively as to the sociodemographic variables and clinical characteristics of the sample. The data of the clinical variables will be analyzed by statistical software SPSS 23.0 for Win. After the normality test, Analysis of variance (ANOVA) followed by Tukey’s test will be applied when necessary and for the treatment results in the study periods, the paired https://dataverse.harvard.edu). The metadata will be published on the site in the repository via the electronic address provided by the platform (DOI).The data collected during the research will be stored and organized in the Harvard Dataverse repository . However, the observed benefits of the interventions may be delimited to a very particular category of participants who met the strict criteria for inclusion or selective exclusion of these patients.This research with a pragmatic trial is justified to respect the features of multimodal treatment of orofacial pain and promote improvement in the quality of life of individuals with TTH and TMD since the literature has already demonstrated the effectiveness of photobiomodulation in explanatory trials.The aim is to reproduce the conditions found in the clinical routine, since simplified procedures but complex elaboration, derive few or no changes in the clinician’s work routines. The control of variables in the analyses of the results will be done using statistical tests and subgroup evaluations. This pragmatic clinical trial should be seen as complementary to explanatory trials in producing evidence and aiding clinical decision-making.Persistent symptoms after COVID-19 infection should be treated with care and concern for the patient’s well-being. The results of this study may support clinical choices and decision-making regarding noninvasive and non-pharmacological adjuvants for the control of tension-type headache and TMD-related orofacial pain. It is expected that the tested protocols will be evaluated for their effect on analgesia, compliance to treatment by the patient, and comfort in the application. The results will serve as input for the development of clinical protocols and therapeutic guidelines.Conceptualization: Mayra Costanti Vilela Campos, Kristianne Porta Santos Fernandes, Raquel Agnelli Mesquita Ferrari, Anna Carolina Ratto Tempestini Horliana, Sandra Kalil Bussadori, Lara Jansiski Motta.Designed the study and wrote the study protocol: Mayra Costanti Vilela Campos, Silvana Simoes Velloso Schuler, Pamella de Barros Motta, Adriana Cátia Mazzoni, Kristianne Porta Santos Fernandes, Raquel Agnelli Mesquita Ferrari, Anna Carolina Ratto Tempestini Horliana, Sandra Kalil Bussadori, Lara Jansiski Motta.Funding acquisition: Mayra Costanti Vilela Campos and Lara Jansiski Motta.Methodology: Mayra Costanti Vilela Campos, Pamella de Barros Motta, Francine Cristina da Silva, Manoela Domingues Martins, Lara Jansiski Motta.Project administration: Mayra Costanti Vilela Campos, Silvana Simoes Velloso Schuler, Adriana Cátia Mazzoni, Lara Jansiski Motta.Writing – review & editing: Mayra Costanti Vilela Campos, Silvana Simoes Velloso Schuler, Pamella de Barros Motta, Adriana Cátia Mazzoni, Francine Cristina da Silva, Manoela Domingues Martins, Kristianne Porta Santos Fernandes, Raquel Agnelli Mesquita Ferrari, Anna Carolina Ratto Tempestini Horliana, Sandra Kalil Bussadori, Lara Jansiski Motta.


The study of gender-related peculiarities of vertebral pain syndrome course in order age patients appears to be highly relevant.Study population included 46 female patients and 38 male patients in the age between 60 and 75 years old; mean age was 67,4±6,6 years old.Pain syndrome intensity was assessed using the visual analogue scale (VAS), vegetative disfunction was assessed using A.M. Wayne Questionnaire; the Toronto Alexithymia ScaleThe conducted comparative study showed that the male patients perceived the pain syndrome as more intense as compared to the female patients in lumbar spine: 4,5 ±0,8 vs 3,6±0,5 scores  and in thoracic spine: 4,1 ±1,0 vs. 3,4±1,0 . On the other hand, in vegetative dysfunction assessment, the male patients demonstrated generally lower score: 43,3±7,5 scores vs. 59,6+10,3 in female patients, р <0,001. The results of correlation analysis pf interrelations between alexithymia and pain intensity revealed the differences between the study groups in emotion recognition accuracy : female patients showed lower scores  as compared to the male patients .Therefore, the vertebral pain syndrome tends to be more pronounced in older age male patients as compared to the similar population of older age female patients. Therefore, vertebral pain syndrome correction requires multidisciplinary approach, including psychotherapeutic support.


The symptomatology in Burning Mouth Syndrome (BMS) is complex and it should be considered in accordance with a biopsychosocial model.To evaluate the multidimensional aspects of pain with a complete battery of tests and to analyse its relationship with potential predictors such as mood disorders, sleep and quality of life.Forty patients with BMS versus an equal number of age and sex‐matched healthy controls were enrolled. The VAS, SF‐MPQ, BPI, PD‐Q, BDI‐II, STAI, PSQI, ESS, SF‐36 and OHIP‐14 were administered.p < .001**). A strongly linear correlation between pain  and disease onset  was found. In the multiple regression analysis, the contributions of the BDI‐II and OHIP‐14 were found to be statistically significant with the SF‐MPQ, PD‐Q and BPI in terms of severity and interference, while the contributions of the STAI and sleep were found to be statistically significant with the SF‐MPQ and BPI in terms of severity and interference, respectively.The scores of the VAS, SF‐MPQ, BPI, PD‐Q, BDI‐II, STAI, PSQI, SF‐36 and OHIP‐14 were statistically significantly higher in the BMS patients than the controls  is complex and it should be evaluated considering the multidimensional aspects of pain in accordance with a biopsychosocial model. 40 patients with BMS versus 40 healthy controls were enrolled and the VAS, SF‐MPQ, BPI, PD‐Q, BDI‐II, STAI, PSQI, ESS, SF‐36 and OHIP‐14 were administered. The results showed that pain tests are differently correlated with mood and quality of life showing that a complete analysis of the patient requires several tools to better understand the multidimensional aspects of pain in BMS. In accordance with the International Classification of Oro‐facial Pain, 1st edition (ICOP 2020),The main symptom reported by patients affected by BMS is pain.Pain manifested in the physical and anatomical dimensions is characterised by psychological, social and cultural dimensions that affect the subjective experience of pain in a biopsychosocial context. The complete analysis of the symptoms of BMS and of the way in which they can affect the life of the patient is very complex and continues to be a challenge for clinicians. For this reason, various questionnaires have been used in the assessment of pain in patients with BMS in order to evaluate every feature of this multidimensional symptomatology.Traditionally, the Visual Analogue Scale (VAS),Until now, few studies have investigated the pain experience of patients affected by BMS through a comprehensive pain assessment including several questionnaires, taking into account also the psychological profile of the patients and analysing the potential predictors of pain.22.1This was an observational case‐control study, which was conducted at the Oral Medicine Department of the University of Naples ‘Federico II’ in accordance with the ethical principles of the World Medical Association Declaration of Helsinki. It was approved by the Ethical Committee of the University . The adopted methods conformed with the Strengthening of the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for observational studies.The target sample size equal to 40 patients for each group (BMSs and controls) was set by fixing a power test value (1‐Beta) no less than 99% associated with a significance of no more than 1%. This sample size was carried out using the effect size value of 1.49, measured in a previously published research study regarding the PSQI scale.At the beginning 90 participants were recruited, aged 55–75 years. They included patients from our group suffering from BMS at the first consultation who had never been treated and, in addition, healthy subjects presenting for routine dental treatment during the study period. Every eligible subject was invited to participate in this study and provided written informed consent. No payment was provided for participation. The patients with BMS and the controls were enrolled in order to match the sample by age, gender and educational level. At the baseline appointment (time 0), 46 patients in the study group and 44 in the control group were considered eligible for this study. At the end of this process, considering the target sample size, 40 individuals in each group met the inclusion and exclusion criteria.patients experiencing an intra‐oral burning or dysaesthetic sensation, recurring daily for more than 2 h per day for more than 3 months, without evident causative lesions on clinical examination and investigation; the pain has the characteristics of burning quality and is experienced superficially in the oral mucosa;patients, male or female, aged at least 18;patients with normal blood test findings ;patients who are not currently in treatment with psychotropic drugs.In accordance with the International Classification of Oro‐facial Pain (ICOP 2020) 1st edition,patients suffering from diseases that could be recognised as a causative factor of BMS;patients unable to understand or complete the questionnaires;patients having a history of a psychiatric disorder or a neurological or organic brain disorder;patients undergoing treatment with psychotropic drugs or systemic drugs possibly associated with oral symptoms;patients having a history of alcohol or substance abuse;patients suffering from obstructive sleep apnoea syndrome (OSAS).The BMS group exclusion criteria were:subjects without any lesion of the oral mucosa;subjects referring to the dental clinic for routine dental care without acute/chronic pain;subjects, male or female, aged at least 18;subjects without a psychiatric disorder or a neurological or organic brain disorder;subjects without a history of BMS;subjects with normal blood test findings ;subjects who had not undergone treatment with psychotropic drugs.The inclusion criteria of the healthy subjects were:subjects unable to understand or complete the questionnaires;subjects having a history of alcohol or substance abuse;subjects suffering from OSAS.The exclusion criteria of the healthy subjects were:2.2At their first consultation, all the participants underwent a careful medical analysis, specifically an intra‐ and extra‐oral examination by an expert clinician in oral medicine (DA). Their gender, age, years of education, family situation, job status, disease onset (in years), sleep duration (in hours), risk factors , oral symptoms and their location, medical comorbidities and systemic drugs taken were recorded and their Body Mass Index (BMI) was calculated.In addition, the patients and controls underwent the following battery scales for a complete analysis of any pain experienced and their psychological profile and QoL Figure .2.3The Visual Analogue Scale (VAS)The short form of the McGill Pain Questionnaire (SF‐MPQ)The Pain DETECT Questionnaire (PD‐Q)The Brief Pain Inventory (BPI)2.42.4.1The Beck's Depression Inventory (BDI‐II)2.4.2The State–Trait Anxiety Inventory (STAI)2.4.3Subjective sleep quality and daytime sleepiness were evaluated using the Pittsburgh Sleep Quality Index (PSQI)2.52.5.1The 36‐Item Short‐Form Health Survey (SF‐36)2.5.2The OHIP‐142.6The R software (v. 4.1 2)  was used to perform the statistical analyses. Descriptive statistics, including means, standard deviations (SD), medians and interquartile ranges (IQR), were measured to analyse the socio‐demographic and clinical characteristics of the two groups. To assess the significant differences between the percentages in the two groups, Fisher's exact test was used.U‐test was performed to test any differences between the clinical parameters, psychological profile, sleep and QoL and to evaluate the recorded medians of the VAS, BPI, PD‐Q, SF‐MPQ, S‐STAI, T‐STAI, BDI, PSQI, ESS, SF‐36 and OHIP‐14. A dependency analysis among the pain tests and qualitative predictors in the BMS patients was computed. The Mann–Whitney U‐test was used to measure the dependency between the pain tests and gender, marital status, employment status, smoking and alcohol consumption. Spearman's linear correlation analysis was tested between the pain tests  and qualitative predictors  measures the effect of the Yes response on the outcome estimation. The demographic model (model 1) was computed to test the contribution of the demographic variables to the pain symptoms. Next, model 2 also considers the disease onset, model 3 the S‐STAI and T‐STAI, model 4 the BDI‐II, model 5 the sleep duration, model 6 the PSQI, model 7 the SF‐36 components and model 8 the OHIP. Each model was computed after controlling for demographic variables to test the contribution of the pain variables to the VAS, SF‐MPQ, PD‐Q, BPI severity and BPI interference, respectively.p‐value <.05 (two‐tails) was considered statistically significant. A post hoc power calculation was performed for the Mann – Whitney test. Considering the analysis of the different tests, the effect size ranged from 0.69 to 0.76 for a sample size of 40 participants in each group, with a significance level of 0.05. The power test value (1‐Beta) was from 0.91 to 0.97 .Finally, a standard regression analysis (model 9) was computed by entering all the variables simultaneously into the model to estimate the relative contributions of all the variables to the pain symptoms. In all the steps, standard errors of the model coefficients, which measure the statistical precision of the inference estimation of the model parameters, are provided. The R software (v. 4.1 2) was used to conduct all the statistical analyses in this study, and a 3p‐value .020*) in addition a significantly higher proportion of the BMS patients were habitual moderate alcohol consumers compared to the controls . In addition, no statistically significant differences were found in relation to the prevalence of systemic diseases and drug consumption between the cases and controls.The socio‐demographic characteristics, the prevalence of systemic diseases and the drug consumption of the sample are shown in Table Comparisons of the clinical parameters between the BMS patients and controls are summarised in Table p‐value <.001**). In detail, in the BMS group 37 patients (92.5%) and 34 patients (85%) had a S‐STAI and T‐STAI score higher than 40, respectively, while in the healthy group only 18 subjects (45%) and 22 subjects (55%) had these scores, respectively, such scores being greater than the predictive threshold value. These results suggest that the majority of patients with BMS are affected by anxiety, both trait and state. Considering the BDI‐II test, the median and IQR range of the scores in the BMS group were 15 and , respectively.In addition, the BMS patients showed statistically significant differences in the medians and IQRs of the scores of the STAI and BDI‐II (p < .001**) and in the three component scores . Poor sleep (PSQI > 5) was found in 30 BMS patients (75%) while only in 21 of the healthy subjects (52.5%). Although no statistically significant differences were found in the ESS total score between the two groups. Statistically significant differences were found in the median and IQR of the SF‐36 sub‐items  and in the total score of OHIP‐14 (p < .001**) between the patients and controls, suggesting an impairment in the HRQoL and Oral health‐related quality of life (OHQoL) of the BMS patients.8 (20%) BMS patients did not show any clinical depression (score < 10) while 19 (47.5%), 10 (25%) and 3 (7.5%) patients presented mild depression (score: 10–18), moderate depression (score: 19–29) and severe depression (score > 30), respectively. Regarding sleep evaluation, the BMS patients showed a strongly statistically significant difference in the PSQI total score  and physicians  were the most frequent doctors consulted. Regarding the causes of disease attributed by the patients; in the majority of cases the onset of the BMS symptomatology appeared after dental treatment  or after a stressful life event .p‐value: .031*) and between sleep duration and VAS, SF‐MPQ and BPI severity and interference . A strongly statistically positive correlation was found between disease onset, S‐STAI, BDI‐II with all the pain questionnaires  and between T‐ STAI with VAS, SF‐MPQ, PD‐Q and BPI severity and interference . A positive correlation was found between PSQI and VAS, SF‐MPQ, BPI severity and BPI intensity  while ESS correlates only with PD‐Q  and BPI severity . In addition, a strongly statistically positive correlation was found between every component of the SF‐36 and OHIP‐14 total score and all the pain questionnaires. Evaluating the qualitative predictors there is a significant positive correlation only between marital status and the VAS scale .The linear correlation analysis between the VAS, SF‐MPQ, PD‐Q, BPI severity and BPI interference and the quantitative and qualitative predictors in the BMS patient group is summarised in Table β: 0.44 p‐value: .016*; β: 0.50 p‐value: < .001**; and β: 0.52 p‐value: < .001**, respectively) resulting in a significant increase in the R2 value . In the third model (PD‐Q); the contribution of BDI‐II and OHIP‐14 was found to be positively correlated with PD‐Q in the BMS patients  resulting in a significant increase in the R2 value . In the fourth model (BPI severity) the contribution of BDI‐II, ESS and OHIP‐14 was found to be positively correlated with BPI severity in the BMS patients  resulting in a significant increase in the R2 value . In the fifth model (BPI interference) the contribution of BDI‐II, PSQI and OHIP‐14 was found to be positively correlated with BPI interference in the BMS patients  resulting in a significant increase in the R2 value .The results of the simultaneous multiple linear regression analyses for the BMS patients, predicting the VAS, SF‐MPQ, PD‐Q, BPI severity and BPI intensity, are summarised in Table p‐value: .045*; DR2 = 52.1% p‐value: .011*; and DR2 = 57.2% p‐value: .003**, respectively).The final full model (model 9) tests the contribution of all the demographic variables and confounding factors, entered simultaneously, to pain. In SF‐MPQ, in BPI severity and in BPI interference the final model was found to be statistically significant . The most frequent additional symptoms reported by our samples were xerostomia, a change in the tongue morphology and dysgeusia, in line with previous studies.Instead, in this study, from the analysis of the pain quality, the median and IQR of the SF‐MPQ assessment was 5 [3–7.25] in the BMS patients, a result considered to be elevated, as compared with the study of RiordainMoreover, the median and IQR of the PD‐Q score of the BMS patients in this sample was 8 [4.75–11.2] and only in 3 patients (7.5%) could the pain be considered as neuropathic (PD‐Q > 19). This result is in accordance with the study of Boku et al.p‐value < .001**). However, in the multiple regression analysis this correlation of both mood disorders remained significant only when considering the quality of pain (SF‐MPQ); at the same time, depression strongly correlated with PD‐Q, BPI severity and interference. In accordance with the study of Schiavone et al.,These results suggested a high prevalence of anxiety and depression in BMS patients in accordance with a recent systematic review and recent observational studies.Regarding sleep evaluation, in line with the studies of Adamo et al.,Anxiety, depression and sleep disturbance are the most important critical psychological factors, which contribute to the modulation and aggravation of the pain experience in BMS, as suggested in several previous studies. Although mood disorders, poor sleep and pain may individually increase the other conditions, all these factors combined lead to a vicious cycle that perpetuates all the other problems.Moreover, in line with a recent systematic review of Pereira et al.,Pain dimensions continue to be one of the most frequently assessed outcome domains in every study about BMS.The BPI is a simple tool, effective in the measurement of pain interference, intensity, location and, possibly, the effectiveness of the therapy.Moreover, considering that QoL was the second most important domain according to the IMPACCT recommendations, clinicians should consider the SF‐36 and OHIP‐14 as additional tools to complete the analysis.Regarding the evaluation of the psychological profile, the choice of using self‐administration tools, such as the BDI‐II, STAI, PSQI and ESS, seems to be adequate in the assessment of anxiety, depression and sleep disturbance in BMS.The study presents some limitations. First, the small sample of the study, consisting predominantly of women and performed in a single centre, should be acknowledged. The limited sample size of this study does not allow the obtainment of a complete pain assessment and an understanding of the relative contribution of each feature. Secondly, the pain scales used were not able to evaluate the pain during the last 6 months and the differences in the duration of the disease may have influenced our results. Thirdly, it was not clear whether the onset of the sleep disturbance and mood disorders was antecedent to the pain, or the contrary, and no pain catastrophising scales were used. Moreover, the study started previously of RDC criteria publication5The results of the current study show that patients with BMS suffer a high level of pain and that this type of pain, in terms of intensity and quality, seriously interferes with the individual's life activities. Mood disorders, sleep quality and QoL are differently correlated with the pain questionnaires and these factors may contribute to the pain experience. However, the significance of the role of the psychological constructs on the pain experience remains unclear.In particular, depression could play a critical role in the pain experience of BMS patients. Conversely, demographic and risk factors, BMI, disease onset and sleep duration did not correlate with pain.The complexity of the symptomatology in BMS patients dictates the need to evaluate the intensity of pain using not only unidimensional tools, such as the VAS, but also multidimensional questionnaires, such as the SF‐MPQ and BPI, in order to better understand the quality and interference of pain. In addition, self‐administration questionnaires, such as the BDI‐II, STAI, PSQI, ESS, SF‐36 and OHIP‐14 should be considered for a comprehensive assessment of the psychological profile and QoL in patients affected by BMS.FC and DA conceptualised the study, EC defined the methodology; FC and EC performed the data collection; LDA and MA performed the statistical analysis; GP, GM and PS participated in conceptualisation of the study and participated in manuscript editing. FC, EC and DA drafted the manuscript; MDM, DA and GP participated in defining the methodology and in manuscript editing; MDM and DA contributing to the scope of discussion. All authors approved the final version of the manuscript.The authors have no conflict of interest, no financial support and no off‐label or investigational use to declare.Figure S1Click here for additional data file.


Acupuncture has been used by rehabilitation specialists as an adjunctive treatment for the symptomatic treatment of rheumatoid arthritis (RA). This meta-analysis aims to evaluate the efficacy of acupuncture in treating patients with RA.  A comprehensive search was conducted in CBM, CNKI, PubMed, CENTRAL, Web of Science, and Embase from their inception up to March 2022. All randomized controlled trials (RCTs) without the language restriction, concerning the patients with RA treated with acupuncture, were included. Two reviewers independently assessed the risk of bias with the Cochrane Risk of Bias Assessment tool. Weight mean difference (MD) and 95% CI were calculated, and data were pooled with random effects model. P=0.040), health assessment questionnaire , physician global assessment , tender joint count , C-reactive protein , and erythrocyte sedimentation rate , while compared to control group. Laser acupuncture could reduce HAQ , the RA quality of life questionnaire , CRP , and interleukin-6 , while compared to control group. No adverse events associated with acupuncture were reported.  A total of eleven RCTs involving 796 patients with RA met the established inclusion criteria. This systematic review indicated the efficacy of acupuncture as an adjunctive treatment for patients with RA. Invasive acupuncture could reduce significantly in pain (MD = -1.00, 95% CI: −1.96 to −0.05,  Available evidence suggests that acupuncture is beneficial for relieving pain and ameliorating quality of life and health index in patients with RA; thereby, it should be available as an adjunctive nonpharmacological treatment in rehabilitation programmes. Rheumatoid arthritis (RA), as a chronic inflammatory autoimmune disease, is manifested by pain, stiffness, swelling, and impaired joint function in the peripheral joints . This chBi” syndrome caused by the invasion of wind, cold, dampness, or heat pathogen into the body's meridians, and then affects joints, bones, and muscles, manifested as articular pain, swollen, stiffness, and even deformity. Acupuncture has been used to treat “Bi” syndrome for thousands of years based on traditional Chinese medicine theory, but its mechanism of action has not yet been elucidated. Current study indicated that acupuncture provided nonanalgesic effect mainly via suppressing the inflammatory response, improving blood flow, and relaxing muscle tone [Acupuncture is a unique treatment method based on the practice of traditional Chinese medicine, in which needles are inserted into certain specific locations of the exterior body, namely acupoints, to relieve pain or for other therapeutic purposes. Based on the theory of traditional Chinese medicine, RA is diagnosed as “cle tone , which nThere are relatively few systematic reviews and meta-analyses supporting the application of acupuncture to the symptomatic treatment of the patients with RA, and these evidences have methodologic concerns and suspicious conclusions about the effectiveness of acupuncture on the treatment of RA. Besides, these studies were mainly systematic review of randomized controlled trials (RCTs) without meta-analysis, and most recent systematic review on clinical efficacy of acupuncture for the treatment of rheumatoid arthritis is about five years ago. Hence, this meta-analysis aims to summarize the latest state of scientific evidence based on published RCTs worldwide and potentially find scientific proof that will allow us to conclude whether acupuncture is effective in relieving pain and improving the quality of life in patients with RA.We followed strictly the recommendations of the Cochrane Collaboration and the PRISMA  guidelines to perform this meta-analysis. A comprehensive literature review was conducted to identify all data on the clinical efficacy of acupuncture treatment in patients with RA from published RCTs.Systematic literature search was performed in Chinese Biomedical Database (CBM), CNKI, PubMed, CENTRAL, Web of Science, and Embase to identify available studies up to March 2022. The search strategy focused on rheumatoid arthritis and acupuncture and was limited to humans and RCTs published in Chinese and English. All bibliographic references cited in RCTs and meta-analysis of interest were tracked to identify additional citations that were not identified through the above search strategy.RCTs using acupuncture as the treatment of RA.Patients (more than 18 years old) with RA diagnosed by physician based on the diagnostic criteria of the European League Against Rheumatism and American College of Rheumatology.Studies intervened with needle acupuncture with or without electrical stimulation or moxibustion, or laser at precise locations to stimulate acupoints for the purpose of treatment. The control group received the same interventions as the acupuncture group, except for acupuncture, or penetrating sham acupuncture.The primary outcomes included C-reactive protein (CRP), health assessment questionnaire (HAQ), visual analogue scale (VAS) of pain, and the RA quality of life questionnaire (RAQoL). If possible, secondary outcomes, such as swollen joint count (SJC), tender joint count (TJC), physician global assessment (PhGA), erythrocyte sedimentation rate (ESR), and interleukin-6 (IL-6), were also measured and assessed.Two reviewers (H.L. and S.M.) independently extracted the data of all eligible studies, and other two reviewers (L.Z. and L.H.) checked the extracted results. Any discrepancy was settled through discussion and consensus, with the third reviewer acted as an adjudicator (H.S.), if necessary. Furthermore, we collected general information on each available study such as authors' name, study design, country, year of publication, sample size, age and sex distribution of patients, and intervention characteristics (such as details and duration of interventions and controls and follow-up) and their outcomes.The risk of bias for all eligible studies was independently evaluated by two reviewers (H.L. and S.M.) according to the Cochrane Risk of Bias Assessment tool, version 2. It was mainly evaluated through the following domains of each study: randomization, allocation concealment, blinding, incomplete outcome data, selective reporting, other biases such as baseline imbalance, and funding. We evaluated the risk of bias for each available study as low risk of bias, high risk of bias, and unclear risk of bias due to uncertainty on the potential bias or lack of information.R software version 4.0.2. Weighted mean difference (WMD) and its 95% confidence interval (CI) were calculated for the mean changes from the baseline of outcomes in the acupuncture group and control group. The Cochran Q statistic test was used to assess the heterogeneity across RCTs. The heterogeneity was quantified with the I2 index. If I2 value was over 50%, substantial heterogeneity was considered to exist [P < 0.05 was interpreted as significant.This meta-analysis was conducted based on at least two studies with to exist  and consWe identified initially 2408 unique citations located through these databases. In our first selection round, 1823 records were potentially related to our topic, with 61 being considered eligible for a full-text review. Eleven RCTs ultimately met the inclusion criteria for this meta-analysis –17. All All the included studies were published between 2006 and 2021. Of 796 patients in the eligible eleven studies, 402 patients received acupuncture , and 394 patients received control interventions . The average age of the included studies ranged between 46.5 and 69.1 years. The main characteristics of all the selected studies are summarized in The results of the risk of bias assessment of the eight studies are illustrated in P=0.040) .Six trials reported pain experienced by patients using VAS –10, 13. P=0.040) . HoweverP=0.028)  .P < 0.001) (P < 0.001), and laser acupuncture had also significantly better effects in ameliorating health status . Besides, subgroup analysis based on invasive or noninvasive intervention in the control group showed that invasive acupuncture had significantly better effects in ameliorating health status   . SubgrouP=0.005) .Seven trials reported tender joint count (TJC) , 16, 17.P=0.005) . SubgrouP=0.580) .Six trials reported swollen joint count (SJC) –10,14,17P=0.580) . BesidesP=0.023) (P=0.019), and laser acupuncture had also significantly better effects in reducing CRP .Eleven trials reported CRP –10,13–17P=0.023) . SubgrouP=0.032) .Nine trials reported ESR –10,13–17P=0.032) . SubgrouP=0.003)  .P < 0.001) .Four trials reported PhGA ,9,14. Th< 0.001) . SubgrouNo adverse effects associated with acupuncture were reported.RA, as an autoimmune musculoskeletal disease, mainly manifests as symmetrical persistent synovitis, rheumatic pain, and destructive polyarthritis involving synovium ,19. WithBi” syndrome, that is, it means that blockage of the meridians caused by any disease pattern to occur due to wind cold dampness evil invading the fleshy exterior and joints, manifesting as some specific symptoms like sinew pain, joint pain, and bone pain, as well as numbness or heaviness of patient's limbs [xue) stasis for arthritis patients such as osteoarthritis. Acupuncture is defined as stimulating a certain point or certain points on the body, known as acupoints, through the insertion and twisting of the needles to achieve desirable therapeutic effects. This is believed to be able to change or prevent the perception of pain or to modify psychophysiological functions to some extent, including pain and mental controls for the treatments of certain diseases or physical dysfunction. Some authors have already used different acupuncture manipulations, such as moxibustion, needle-sticking method, warm needling, plus herb steaming, and reinforcing-reducing/twirling-reinforcing needling to treat certain chronic painful diseases, and achieved better clinical efficacy [According to the theory of traditional Chinese medicine, RA patients should meet the conditions of so-called “'s limbs . Acupuncefficacy –24. In aefficacy ,25–27.Acupuncture seems to be a promising treatment while compared to conventional current RA medication. Our meta-analysis indicated that the selected acupoints were obviously different among these clinical studies, and the most commonly used acupoints were ST36 (63.6%) and LI11 (45.5%). Most studies showed that acupuncture could improve pain, although some studies did not indicate statistical significance, except for the study by Tam et al. Besides, this meta-analysis also pointed out that the use of acupuncture might ameliorate the HAQ, RAQoL, PhGA, tender joint count, and inflammatory markers of patients with RA, while compared to control management strategies. Traditional Chinese Medicine treatment follows the people-centered principle, so the treatment protocol of acupuncture is not fixed, and it is always adjusted according to the different Traditional Chinese Medicine syndrome patterns that corresponded to different biological processes. In the treatment protocol of Zukow et al., 20 acupoints were selected and the subsequent treatment was adjusted according to the patient's symptoms, and the results showed that acupuncture was superior to sham acupuncture in pain improvement. The study by David et al. selected only one acupoint (LI3) to observe the therapeutic effects of acupuncture and concluded that acupuncture was ineffective in relieving patients' pain. They themselves believed that the acupoint LI3 may be an incorrect or inadequate point on its own to use in order to show an effect in RA. This meta-analysis results showed that there was heterogeneity among many research results, which may be related to the selection of acupoints, operation technology, course of treatment, and acupuncture combined with other therapies.α, and IL-6. Besides, it can also decrease oxidative stress, improve tissue oxygenation, and relieve pain [α in joint synovia and peripheral blood and ameliorate the internal environment of the body, which is very benefit to patients with RA [In patients with RA, the core mechanism of chronic nociceptive pain is thought to be inflammation. In patients with RA, inflammatory mediators generally tend to accumulate in the synovial fluid of the joints, and then, these inflammatory mediators can directly activate the nerve terminals within these joints, leading to the release of neurotransmitters and the transmission of pain messages and consequently to inflammatory pain. Previous studies have indicated that the acupuncture at acupoints can induce certain cells proliferation and migration, especially for fibroblasts, and modulate the production and secretion of cytokines, growth factors, and inflammatory mediators such as CRP, TNF-eve pain ,29. It heve pain . Acupunceve pain ,31. Besieve pain . This isIn addition, studies suggested that acupuncture may work by stimulating the serotonergic, noradrenergic, and opioid system and promoting the release of endorphins, which may help relieve pain and increase feelings of well-being and relaxation in this way ,34. It iThere are several limitations to consider. First, as shown in In summary, this meta-analysis shows that acupuncture is beneficial for relieving pain and ameliorating the quality of life and health index in patients with RA; thereby, it should be available as an adjunctive nonpharmacological treatment in rehabilitation programmes. In addition, due to limitations of paucity and suboptimal methodology of the primary studies, our findings need to be verified by some studies with larger cohorts and longer follow-up periods.