Objective: The purpose of this research is to assess the analgesic efficiency of Photobiomodulation (PBM) in pain reduction in young patients during rapid maxillary expansion therapy. Materials and Methods: Thirty patients were included and allocated to an experimental group [Rapid Palatal Expansion (RPE) and PBM] and a control group (RPE only) at random. Inclusion criteria were skeletal age from CVS1 to CVS3, examined on the cephalometric lateral teleradiography, with cervical vertebra staging and completed eruption of upper first molar. Exclusion criteria were previous orthodontic treatment, bone disease, disability, or skeletal age from CVS4. Patients referred the pain they felt using a Numerical scale rate (NRS), ranging from 0 to 10, with specific intervals of time: 6 h, 12 h, 24 h, and from days 2 to 7. The Wilcoxon-Mann-Whitney test was used to evaluate differences in NRS reported values between the two groups. Results: The final sample included 30 patients, 14 males and 16 females, with a mean age of 7.8 ± 1.2 years. The pain that was felt at each time interval and the maximum score of pain were significantly lower in the experimental group (p < 0.05) and decreased faster in the experimental group, with a score test near to 0 after 2/3 days. Conclusions: PBM is efficient in reducing the intensity and the time of pain felt by young patients that undergo rapid maxillary expansion. Rapid maxillary expansion (RME) is the treatment of choice for the correction of transversal maxillary deficiency and posterior cross-bite in growing subjects . This trConcerning patients’ experience, previous evidence would suggest that pain is the symptom mostly reported, with a frequency >90% among children . OrthodoPhotobiomodulation is a therapy with many different applications in medicine and dentistry and it is free of side effects ,18. It cThe present randomized clinical trial, with single operator and parallel groups (1:1) was performed with respect to the Declaration of Helsinki of 2013. This study does not have a clinical trial registration number, because it is a strictly observational study: we simply reported the pain perceived by patients undergoing rapid palatal expansion treatment, some who had a Photobiomodulation session with ATP38 , and some who did not. We did not measure the pain with any device, we limited ourselves by pain reported by patients.Patients were chosen and treated in the period between April 2019 and March 2020, and they all signed an accurate informed consent.Patients were chosen following these criteria: (1) skeletal age from CVS1 to CVS3, determined with the cervical vertebra staging on the cephalometric lateral teleradiography, (2) complete eruption of the first upper molars, and (3) clinical need to undergo an RPE. Some patients were excluded following these other criteria: (1) skeletal age from CVS4, (2) craniofacial disorders or bone diseases, (3) orthodontic treatment in the past, and (4) disability.Patients were divided at random into a group that received RPE and LED irradiation and group that received RPE only following a randomized balanced block protocol that had sex and ages as stratification factors.Patients belonging to the control group were treated without LED irradiation at the Odontostomatology department of the San Gerardo Hospital of Monza (University of Milan-Bicocca). As for the patients belonging to the experimental group, they were treated with LED irradiation in a private clinic in the province of Bergamo.For randomization purposes, we used the SPSS Statistics software  to generate an allocation sequence.A total of 151 patients were recruited from a larger sample of patients, 117 of whom were excluded because the inclusion criteria were not met.Of the remaining 34 patients, 18 were assigned to the experimental group and 16 to the control group . This di®   of each of the three active panels (16 J/cm2 × 3 = 48 J/cm2). These standards are based on a specified distance of 4 cm of the side panels from the cheeks and of the side panel from the lips. We used 3 consecutives cycles of PBM, because 48 J/cm2 are lower than the fluence range used for orthodontic PBM, for an overall time of 18 min and 144 J/cm2 of fluence (48 J/cm2 × 3 cycles) with 1 min suspension between each cycle. The level of pain perceived by each participant was assessed with the NRS  at a distance of 6, 12, 24 h, and after each day up to the seventh day from the positioning of the expander in situ. Verbal instructions were provided to parents and young patients on how to correctly evaluate the perceived pain level, to indicate on the scale a value from 0 or absence of pain to 10 or the maximum pain imaginable. No one of those analyzed used analgesics or anti-inflammatory drugs during the active expansion phase. The collection, processing, and storage of data took place through electronic questionnaires, which can be filled in online and were accessible to each participating researcher. The data were recorded electronically and analyzed.We took the alginate impressions for the execution of the rapid expansion device with bands on the first permanent molars and we cemented them with glass ionomer cement (3M ™ Ketac ™ Cem). We used the same protocol for the palatal expansion for both the test and control groups, 2 activations per day were executed distant 12 h from each other for an overall period of 7 days . No LED biostimulation was performed on the control group. The test group, on the other hand, was treated with LED irradiation at the time of the positioning of the RPE with ATP38 France) . This dep ≤ 0.05.For both test and control groups, gender distribution was analyzed, descriptive statistics, mean, and standard deviation of age were calculated, and data reported on the NRS scale for all time intervals analyzed by T0 (day of positioning of the device in situ) at time T1 (at the end of the first week of activations), with the use of Excel worktables. Using the Shapiro-Wilk normality test , the normal distribution of the data obtained was preliminarily checked . Since the data were not normally distributed, a nonparametric test was chosen to evaluate the statistical significance of the analyzed values. The differences in the NRS assess between the experimental and control group at each time record were analyzed by the Wilcoxon-Mann-Whitney nonparametric statistical test . In addition, a linear regression was used to evaluate the effect of timing on pain experienced within the entire period. Statistical significance was set as ® laser protocol, showed the following results.The statistical analysis of the data obtained from the questionnaires completed by the patients of the control group and the experimental group, irradiated according to the ATP38In the test group, the highest perception of pain was at six hours after the expander was placed, with an intermediate scoring of 2, and then it progressively decreased to an intermediate scoring of 1 after 12 h, and 0 from day two .In the control group, the highest perception of pain was at 6 and 12 h after the expander was placed, with an intermediate scoring of 4, and then it initially declined to a median of 3 from 24 h, but then increased again at day three to a median of 4, decreasing to 2 on day four, 3 on day five, 2 on day six, and 1 on day seven .The Mann-Whitney showed that the pain perceived by patients in each moment we recorded and the highest pain scored were significantly different between the two groups . In thisA strong correlation was found between the timing (assessed as multiple follow-up) and pain perceived in control group (R = 0.933) and the experimental group (R = 0.750), according to the linear regression model. The R-squared value, which reflects the percentage of variability in each dependent variable (pain) attributed to the changes of the predictor (time), was 0.852 in the control group and 0.563 in the experimental group .The purpose of this randomized clinical trial was to assess the effects of LED photobiomodulation on pain perception during rapid expansion of the maxilla in growing subjects. Previous studies have analyzed the trend of perceived pain intensity during rapid expansion of the palate showing a peak in the first three days due to the release of the chemical mediators of inflammation and the creation of hyalinization zones, following the application of orthodontic strength. Our results are consistent and confirm this pattern. First of all, we observed that in the literature there were studies that analyzed the effectiveness of laser photobiomodulation in orthodontics during the positioning of elastic separators ,26 or or® allows a simultaneous irradiation of all circummaxillary sutures in clinically acceptable times, difficult to achieve with other types of laser machines managed directly by the operator. The operator dependency parameter, which can certainly represent a bias for the statistical evaluation and a reproducibility constraint of the study itself, was eliminated by the standardization of the irradiation protocol [® device was dictated by the analysis of the biological effects on the tissues, by the analgesic efficacy shown by the LEDs in the literature, but above all by the possibility of eliminating the operator-related bias, with a saving of time useful for the clinician, and the ability to control the setting and parameterization of the instrument itself with extreme precision and reproducibility [Certainly, a first reason lies in the fact that the application of a correct biostimulation must face the technical difficulties inherent in the type of device used. In fact, ATP38protocol . Animal cibility ,40,41. T® laser for reducing orthodontic pain related to RPE for these reasons: (1) demonstrated analgesic effect with no known undesirable effects on tissues, (2) the secondary effects reported with the use of analgesic drugs, and (3) the benefits of an operator-free LED appliance in gaining of time and precision of the device setting provided.According to our statistics, the pain perceived by subjects who endured LED appliance was significantly lower than that experienced in control group. Similarly, the maximum pain score was significantly lower. Based on the study of Farrar et al. , a decre® laser alleviates the intensity and duration of pain perceived by few patients enduring rapid maxillary expansion.LED photobiomodulation with ATP38® could be an important aid for the orthodontist professional in the treatment of young patients with rapid expansion of the palate, as the reduction in the intensity and duration of pain would certainly benefit the patient and their compliance would increase, as well as the parents’ willingness to continue with further orthopedic-orthodontic therapies necessary for a harmonious growth of the dento-facial complex.It follows that the use of LED irradiation with ATP38


Background: Since the management of chronic pain has become even more challenging secondary to the occurrence of SARS-CoV-2 outbreaks, we developed an exhaustive narrative review of the scientific literature, providing practical advices regarding the management of chronic pain in patients with suspected, presumed, or confirmed SARS-CoV-2 infection. We focused particularly on interventional procedures, where physicians are in closer contact with patients. Methods: Narrative Review of the most relevant articles published between June and December of 2020 that focused on the treatment of chronic pain in COVID-19 patients. Results: Careful triage of patients is mandatory in order to avoid overcrowding of hospital spaces. Telemedicine could represent a promising tool to replace in-person visits and as a screening tool prior to admitting patients to hospitals. Opioid medications can affect the immune response, and therefore, care should be taken prior to initiating new treatments and increasing dosages. Epidural steroids should be avoided or limited to the lowest effective dose. Non urgent interventional procedures such as spinal cord stimulation and intrathecal pumps should be postponed. The use of personal protective equipment and disinfectants represent an important component of the strategy to prevent viral spread to operators and cross-infection between patients due to the SARS-CoV-2 outbreaks. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 which can lead to COVID-19 disease) was declared a Public Health Emergency of International Concern on 30 January 2020 and, and as of March 2021, more than 120 million people worldwide have been infected, with more than two million deaths ..28].Adherence to this guidance eased as infection rates decreased, but given the recent dramatic surge in cases worldwide, this recommendation once again becomes quite salient. The evaluation of semi-urgent procedures  entering the facility and anyone positive for a fever > 37.5 °C or respiratory symptoms  is denied access and undergoes testing for SARS-CoV-2. The duration of appointment slots has also been expanded in order to allow sufficient time for disinfection and cleaning following each procedure.Interventional pain procedures reduced opioid consumption , which iThe association between chronic pain and the immune system, and pain’s ability to induce immunosuppression, has long been recognized . OpioidsHowever, it is essential to note that various opioids differ in their effects on the immune system, with morphine and fentanyl having the greatest immunosuppressive action and buprenorphine the weakest ,65,66,67Taking these factors into consideration, therapy may include administration of short-term opioids to patients experiencing acute pain episodes or severe chronic pain aggravation. This is only advised assuming careful risk stratification and appropriate screening for signs likely to signify potential risks for aberrancy. Furthermore, consultation with the prescription drug monitoring program and an exit strategy with which patients are in agreement should be the standard of care. In patients requiring opioid therapy for a period of more than 1 or 2 weeks, an in-person examination is recommended within 4 weeks to allow physicians to assess the severity of the pathology through physical examination, if possible ,73.For patients already receiving high-dosage, long-term opioid therapy, increased opioid treatment for a limited period may be suggested, provided that appropriate risk mitigation practices are utilized. However, we recommend an in-person visit, other than in situations in which doing so is not feasible, within 8 weeks to help identify an advance of the disease process requiring treatment or signs of opioid tolerance or opioid-induced hyperalgesia .Interactions between opioids and antiviral medications should be considered in patients with SARS-CoV-2 infections. Despite conflicting data, Lopinavir/Ritonavir and Remdesivir have been used as a standard aspect of infection treatment for patients admitted with COVID-19 disease. These medications have a profound impact on metabolism of opioids, with Ritonavir inhibiting CYP3A4, which is a key aspect of most opioids’ metabolic pathways. Further, oxycodone plasmatic levels are greatly increased with concomitant lopinavir use , therebyTelemedicine refers to the electronic exchange of medical information through a variety of platforms including telephone consultation, video conferencing and short message services for the delivery of health care services remotely. It is used throughout most of the western nations and seeks in general terms to be analogous to traditional care . ResearcFollowing the appearance of SARS-CoV-2, the role of telemedicine  has becoTelemedicine is also useful for streamlining a series of procedures, such as patient procedural education, preauthorization prior to performing procedures, pre/post-procedural consultation, and intermittent remote outcome monitoring. Even aspects of the physical examination itself can be carried out via video conferences, e.g., when judging appearance and movement, or when conducting self-examination under guidance. An element of considerable interest is the development of telemedicine in determining which patients are emergent, rather than urgent or elective , therebyAs aforementioned, a practical example in which use of remote monitoring or more generally, of telemedicine, is suggested, are the programming and control of spinal cord stimulators remotely or opioid addiction control or dosage adjustment.During the COVID-19 pandemic, a high incidence of psychological distress and symptoms have also been observed, including mental health disorders, posttraumatic stress disorder, psychosomatic disorders, and substance abuse ,89,90.Many suffer from affective disorders (particularly depression), while others suffer from substance abuse, personality disorders, and various somatoform disorders such as conversion, hypochondriasis, and somatization disorder . In some patients, certain of these varied disorders may be secondary to chronic pain, but in others they predate the onset of pain or reflect alternative expressions of the same underlying psychobiological disorder .Furthermore, individual and societal disruption associated with COVID-19 are likely to increase their likelihood of emergence ,92. MoreAs recommended by the WHO, a practical example of psychosocial support during SARS-CoV-2 outbreak would be that provided to older adults. Although always a vulnerable population, those living in isolation and those with cognitive decline/dementia, are prone to becoming more anxious, angry, stressed, agitated and withdrawn during the outbreak or while in quarantine  older adDue to the COVID-19 pandemic, there exists an increased risk of chronic pain patients failing to receive critical treatment. Chronic pain patients may also be at increased risk of COVID-19 disease due to multiple factors, such as chronic opioid therapy potentially making them more susceptible to the COVID-19 infection due to immunosuppression ,57,58,59Based on the limited extant literature in conjunction with our clinical experiences, we suggest that interventional pain management can be reinitiated, albeit cautiously, to more effectively treat chronic pain patient population. As steroids are associated with immunosuppression, as well, throughout the remainder of the COVID-19 pandemic, epidural steroid injections should be performed judiciously and with the lowest possible effective dose . SCS andHowever, we hope that this review serves as source of guidance to chronic pain clinicians in the future, and believe that it will remain relevant, irrespective of the course of the pandemic.


Background: While most previous studies regarding patients with chronic low back pain (CLBP) mainly focused on pain, disability, psychological damage, and intervention measures, the effect of CLBP on personal space remains unclear. The study aimed to assess the personal space of patients with CLBP and healthy controls, explored the differences between the two groups, and examined whether pain, dysfunction, anxiety, and depression affected the personal space regulation.Methods: The cross-sectional study recruited 24 patients with CLBP and 24 healthy controls at Shanghai Shangti Orthopedic Hospital and Shanghai University of Sport, Shanghai, China, from December 2018 to January 2019. A stop-distance paradigm was applied to measure the comfortable and uncomfortable distance under four conditions. A self-rating anxiety scale (SAS) and a self-rating depression scale (SDS) were used to examine the anxiety and depression levels of all participants. The pain intensity and dysfunction in the CLBP group were evaluated by the numeric rating scale and Roland-Morris questionnaire (RMDQ), respectively.Results: When approaching another individual or when being approached, the interpersonal distance under all the conditions in the CLBP group significantly differed from that in the healthy control group with larger space distances (p < 0.01). Gender had a significant main effect on the regulation of personal space in patients with CLBP (p < 0.05). The average pain intensity, scores on RMDQ, SAS, and SDS had a significant positive correlation with the interpersonal distance under the Same or Opposite Gender condition (p < 0.05).Conclusion: People with CLBP show an atypical personal space behavior and indeed have a greater interpersonal distance to strangers. The higher the pain intensity, dysfunction, anxiety, and depression, the greater the interpersonal distance in patients with CLBP. In the future, the effect and underlying neural mechanisms of pain and negative emotions on social withdrawal in patients should be examined. Low back pain (LBP) is defined as pain that occurs between the inferior border of the ribs and the buttock wrinkles, which may be accompanied by lower limb pain or related neurological symptoms , 2. MostSince humans are fully socialized creatures and spend almost 80% of their waking time with other people , socialiPersonal space refers to the perceived comfortable and safe area around individuals. Individuals normally experience discomfort and anxiety if it is intruded . During The study aimed to assess the personal space of patients with CLBP and healthy controls; explore the differences between the two groups; and examine whether pain, dysfunction, anxiety, and depression affected the personal space regulation in patients with CLBP. It is hypothesized that individuals with CLBP avoid to be too close to strangers and have a greater personal space than healthy controls; pain, dysfunction, anxiety, and depression negatively impact interpersonal distance; and patients with CLBP experience social withdrawal in daily life.*Power should have 21 participants in each group . In the present study, 24 patients with CLBP and 24 healthy adults were recruited between December 2018 and January 2019 from the Shanghai Shangti Orthopedic Hospital and Shanghai University of Sport, Shanghai, China. The CLBP group  and the control group  matched in terms of age (23.67 vs. 23.83 years), gender ratio , height (166.38 vs. 167.06 cm), body weight (63.23 vs. 62.23 kg), and body mass index   . All theThe Ethics Committee of Shanghai University of Sport approved this study. All the subjects voluntarily participated and signed their written informed consent forms.Before participating in the study, all the subjects completed a questionnaire on the following details: basic information, CLBP evaluation, and psychological evaluation .In CLBP evaluation, a numeric rating scale  was used to assess the maximum and average pain intensity (NRS1 and NRS2) of the patients who experienced CLBP in the past 3 days. It is a valid, reliable, has good test-rest reliability , excellent responsiveness , and is often preferred tool to measure the severity of pain , 32. Ther = 0.30), and the correlation between the SDS and the Beck Depression Inventory is 0.68  and a self-rating depression scale (SDS). These scales are used to quantify the anxiety and depression level of the subjects. Each scale has 20 items with a score of 1–4 . The normalized score is equal to the total score (ranging from 20 to 80) multiplied by 1.25  . Cronbac is 0.68 . Both sc is 0.68 . The SAS is 0.68 , 39.In social interaction, people can automatically regulate interpersonal distance. With high validity and reliability, a stop-distance paradigm is frequently applied to measure the preferred interpersonal distance under various conditions , 40. At Under the first condition, the unfamiliar experimenter (same gender) slowly walked toward the subject until he or she reached the distance, where the subject would normally maintain a stranger; this distance was denoted as the comfortable distance CD1; . Thereaft-test, and a Wilcoxon rank-sum test. We performed a normality test on all data and normal transformation when necessary. The difference in the interpersonal distance under various conditions between the CLBP and control groups was analyzed through an independent sample t-test. Two-way ANOVA was performed to examine the significant effect of the Approach Direction (being approached or approaching) and Gender (same or opposite gender) on interpersonal distance based on adjusted analysis. Age, body weight, height, and BMI were included in adjusted analysis as baseline covariates. Further associations between interpersonal distance and different clinical indicators  were tested by using the Pearson correlation test with Benjamini-Hochberg adjustment for multiple testing. Adjusted p < 0.05 was considered as statistical significance.Differences in demographical and clinical data between the two groups were explored with a chi-square test, an independent sample t = 3.350, p = 0.002; UD1: t = 3.251, p = 0.002; CD2: t = 3.496, p = 0.001; UD2: t = 3.208, p = 0.003; Under the Same Gender condition, the average CD1 between the subjects and an unfamiliar experimenter was 81.97 ± 25.25 cm in the CLBP group and 61.49 ± 16.11 cm in the control group, and they had average UD1 of 44.15 ± 16.77 and 32.01 ± 8.75 cm, respectively . Under tt = 3.734, p = 0.001; UD3: t = 3.258, p = 0.002; CD4: t = 3.229, p = 0.003; UD4: t = 3.216, p = 0.002; Under the Same Gender condition, the average CD3 between the subjects and an unfamiliar experimenter was 74.63 ± 23.09 cm in the CLBP group and 55.02 ± 12.40 cm in the control group, and they had average UD3 of 40.75 ± 14.51 and 29.68 ± 8.91 cm, respectively . Under tF = 5.187, p = 0.025; F = 11.943, p = 0.001; F < 0.001, p = 0.991; t = −2.203, p = 0.033; Approaching: t = −2.756, p = 0.008). No significant difference in the distance of the Being Approach subgroup and the Approaching subgroup under the Same or Opposite Gender condition .The Approach Direction significantly affected the control group but not the CLBP group [F = 4.293, p = 0.041; F = 2.638, p = 0.108; F = 0.003, p = 0.960; t = −1.609, p = 0.114; Approaching: t = −1.375, p = 0.176; Same Gender: t = 1.068, p = 0.291; Opposite Gender: t = 1.280, p = 0.228).In the CLBP group, Gender showed a significant main effect [F = 23.171, p < 0.001; F = 7.051, p = 0.009; F = 2.954, p = 0.089; F = 1.858, p = 0.176; F = 0.019, p = 0.892; F = 0.002, p = 0.962; t = −3.531, p = 0.001; approaching: t = −3.239, p = 0.002). The distance maintained by the Opposite-Gender subgroup was constantly larger than that maintained by the Same-Gender subgroup. The Being Approach subgroup and the Approaching subgroup did not significantly differ in terms of uncomfortable distance under the Same or Opposite Gender conditions . In the CLBP group, no significant difference was observed between the Same- and Opposite-Gender subgroups or the Being Approached and Approaching subgroups .Gender had a significant main effect in the control and CLBP groups [control group: 6.The results of the correlation analysis between clinical factors  and interpersonal distance are shown in r = 0.473, adjusted p = 0.029), RMDQ , SAS , SDS , and comfortable distance had significant positive associations when the subjects were the same gender as the experimenter , SAS , and distance had significant positive associations when the gender of the subjects and the experimenter were not the same , SAS , and SDS  under the Same Gender condition of the CLBP group , and SDS  under the Opposite Gender condition was significantly positive  and social behaviors. Additionally, considering its bilateral activation is correlated with the perceived pain intensity , the amyInterestingly, the results showed that there is no association between maximum pain intensity during CLBP and personal space. One possible reason is that the maximum pain intensity during CLBP does not have a continuous and stable effect, which might indicate a limited effect of pain on the regulation of personal space in social communication. In the future, studies should explore whether immediate painful stimulation affects the size of personal space.Few studies have explored the effect of CLBP on personal space. This study provided new insight into the personal space management for patients with CLBP, which is practically significant. However, the limitations in the study should be considered. First, the sample size was relatively small. In future experiments, more subjects should be recruited to improve the credibility of experimental results. From the perspective of participant recruitment, a wider age range and more occupational types should be considered to more comprehensively show the results. Second, a stop-distance paradigm as an artificial task may fail to completely and accurately reflect social behavior in real life. As such, tasks that can more validly reflect the personal space during real social interactions should be established. Third, this study only investigated the changes in interpersonal distance between patients with CLBP and strangers. Further studies should examine whether the interpersonal distance between patients and familiar people will be different from healthy controls. Fourth, other factors that may affect social behavior and personal space, such as employment status, socioeconomic status, were not collected in the study. These factors could be considered and included in the next step of research.Our results revealed that the association of CLBP with social withdrawal is worthy to be focused on. This study offered a novel method for assessing the psychosocial status in patients with CLBP. Pain and disability are the most prominent symptoms in CLBP, which makes most patients seek medical attention. Psychosocial problems, which are often overlooked, play an important role in physical and mental health. As such, the psychosocial problems in patients with CLBP should be explored. Medical staff should consider potential social withdrawal and reduced social interactions. They should also formulate the corresponding psychosocial interventions to help patients smoothly reintegrate into society. Additionally, the effect and underlying neural mechanisms of pain and negative emotions on social withdrawal in patients should be examined. In the future, a larger sample size, more realistic social tasks, and more task models  will be needed to explore the effect of CLBP on psychosocial status.People with CLBP show an atypical personal space behavior, indeed have a greater interpersonal distance to strangers and reduced social interactions. The increased anxiety, depression, average pain intensity, and dysfunction in CLBP are related to the greater personal space and more severe social withdrawal. The changes of personal space are one of the manifestations of social behavior. CLBP reduces the connection and interaction between individuals and society and produces social withdrawal and loneliness. In addition to alleviating pain and dysfunction in clinic, social and psychological problems in patients with CLBP during recovery should be explored to accurately identify the difficulties that need improvement. Further research can enhance our understanding of psychosocial changes in patients with CLBP and provide the evidence for the implementation of psychological rehabilitation.The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by Ethics Committee of Shanghai University of Sport. The patients/participants provided their written informed consent to participate in this study.L-MW, BW, and X-QW conceived and designed the study. L-MW, BW, C-CC, JW, and M-SP collected the data. L-MW and BW analyzed and interpreted the data. L-MW drafted the manuscript. BW, Z-JZ, and X-QW revised the manuscript for important intellectual content. All authors discussed the results, commented on the manuscript, and approved the final manuscript.This work was supported by Fok Ying-Tong Education Foundation of China (161092), Scientific and Technological Research Program of the Shanghai Science and Technology Committee (19080503100), Shanghai Key Lab of Human Performance (Shanghai University of Sport) (11DZ2261100), Science and Technology Commission of Shanghai Municipality (21S31902400), and Project of Science Research of Traditional Chinese Medicine of Henan Province of China (2019ZY1028).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Triptorelin is one of the most commonly used gonadotropin-releasing hormone agonists and has been used in the treatment of deep infiltrating endometriosis (DIE). This study aimed to evaluate the efficacy and safety of up to 24 weeks of triptorelin treatment after conservative surgery for DIE.This prospective, non-interventional study was performed in 18 tertiary hospitals in China. Premenopausal women aged ≥18 years treated with triptorelin 3.75 mg once every 28 days for up to 24 weeks after conservative surgery for DIE were included. Endometriosis symptoms were assessed, using a visual analogue scale (0–10 cm) or numerical range (0–10), at baseline (pre-surgery) and routine visits 3, 6, 9, 12, 18, and 24 months after surgery. Changes in symptom intensity over time were primary outcome measures.P = .001) and patients with moderate  or severe  pain versus none/mild pain. Triptorelin was well tolerated without serious adverse events.A total of 384 women  were analyzed. Scores for all symptoms  assessed decreased from baseline over 24 months. Cumulative improvement rates in pelvic pain, dysmenorrhoa, ovulation pain, and dyspareunia were 74.4%, 83.6%, 55.1%, and 66.9%, respectively. The 24-month cumulative recurrence rate (≥1 symptom) was 22.2%. The risk of symptom recurrence was higher in patients with ≥2 versus 1 lesion (odds ratio [OR] 2.539; 95% CI: 1.458–4.423; Triptorelin after conservative surgery for DIE improved symptoms over 24 months of follow up. The recurrence rate of symptoms was low and triptorelin was generally well tolerated.Trial registration number: ClinicalTrials.gov, NCT01942369. The first study focuses on the symptom control of post-operative triptorelin therapy in patients with deep infiltrating endometriosis conducted in multi-centers in China and suggests that triptorelin following conservative surgery was effective and well tolerated.1 Women during the reproductive period are predominantly affected, with the main symptoms being pain  and infertility.–3 The overall prevalence of endometriosis in women of reproductive age is estimated at 2% to 10%.,5 However, the prevalence of endometriosis is 71% to 87% among women suffering from chronic pelvic pain and 50% among infertile women.,7Endometriosis is defined by the presence of endometrial-like tissue outside the uterus, most commonly on the peritoneal and visceral surfaces of the pelvis, which triggers a chronic inflammatory reaction.,9 DIE is the most aggressive of the 3 clinical forms, characterized by deep infiltration and the most severe pain symptoms. Furthermore, it is the most difficult to manage and is associated with high direct and indirect treatment costs.Endometriosis can be divided into 3 types based on severity: superficial peritoneal endometriosis (least severe), ovarian endometriosis, and deep infiltrating endometriosis .,12 However, for one thing, surgery might not completely eliminate the lesion, residual lesions, and new lesions may continue to grow or develop. For another, surgery is associated with the development of pelvic cavity adhesions. Additionally, the reported 3-year symptom recurrence rate following surgery was 38% to 51%.Surgery is the preferred treatment in cases of DIE and the effectiveness of conservative surgery in patients with DIE has been demonstrated. Gonadotropin-releasing hormone agonists (GnRH-a) have been recommended as second-line therapies for improving symptoms. Triptorelin is one of the most commonly used GnRH-a and has been demonstrated to improve symptoms and fertility outcomes of patients with DIE.,16A variety of medical therapies are now available for symptomatic endometriosis.–19 the effectiveness and optimal duration of GnRH-a treatment after surgery in DIE are still debated in China. This study aimed to evaluate whether up to 24 weeks of treatment with triptorelin following conservative surgery can help manage the DIE symptoms, reduce symptom recurrence rate, and improve fertility status over a 24-month follow-up period in clinical practice in China.Although multiple studies have shown that GnRH-a treatment following surgery can improve postoperative pain and may facilitate a reduction in the rate of symptom recurrence,2www.clinicaltrials.gov (NCT01942369).This multicenter, prospective, non-interventional, observational study was conducted in 18 tertiary hospitals in China between September 8, 2013 and July 13, 2018. The study was approved by the Institutional Review Board at Women's Hospital, School of Medicine, Zhejiang University and by ethical committees of all study centers and was registered at 2.1Patients were screened using electronic diagnostic records and were eligible according to the following inclusion criteria: patients who were premenopausal women aged ≥18 years with a clinical diagnosis of DIE; had received conservative surgery within 1 month of the study start date; had been prescribed triptorelin; and were mentally and physically able to describe their symptoms and answer questions. Conservative surgery for the treatment of DIE refers to the removal or destruction endometriosis lesions or nodules, separation of adhesions, removal of ovarian chocolate cyst, and preservation of uterus and ovary, so as to preserve the reproductive function. Exclusion criteria: pregnant or lactating women; premenopausal women who may reach menopause within 3 years of surgery; a history of allergic reaction to triptorelin or one of the excipients; a history of treatment with other drugs within 3 months and GnRH-a therapy within 6 months prior to the study; and women who were potentially non-compliant or unsuitable for the study for other reasons, as judged by the investigator.All included patients provided written, informed consent.2.2Patients received triptorelin acetate 3.75 mg as an intramuscular injection  once in the cycle of 28 days for up to 24 weeks (≤6 injections). The prescription and number of required treatment cycles were determined by physicians based on routine clinical practice, without external intervention. Moreover, other treatments and management of adverse events were in accordance with routine clinical practice.Patients were assessed at baseline (pre-surgery) and then at routine post-operative hospital visits every 3 months in the first year of follow up and every 6 months in the second year of follow up. At each visit, data and information of endometriosis symptoms and pregnancy status, as well as imaging and laboratory examinations were collected.2.3In the Core Outcomes in Women's and Newborn Health database, a core outcome set for endometriosis is currently in development. The primary outcome was changes in intensity/severity of endometriosis symptoms from baseline (pre-surgery) to 24-month follow up. Symptoms of pelvic pain, dysmenorrhea, pain at the time of ovulation, and dyspareunia were assessed using a visual analogue scale (VAS) with a range from 0 to 10 cm, and symptoms of amenorrhea, menorrhagia, metrorrhagia, and gastrointestinal and urinary discomfort were assessed using a numerical scale ranging from 0 to 10. A score of 0 indicated that the patient was free of pain or symptoms, while a score of 10 represented pain or symptoms that were severe and intolerable. Symptoms with a VAS or numerical score >0 and ≤3, >3 and <7, and ≥7 were considered as mild, moderate, and severe, respectively. An improvement in symptoms was defined as a reduction of at least 3 cm or 3 units from presurgery levels. The proportions of patients with symptoms overall and with symptoms of different intensity/severity levels were also assessed.Secondary efficacy outcomes were the rates of symptom recurrence and pregnancy. Symptom recurrence was defined as an increase of >3 cm or 3 units on the VAS or numerical score compared with the lowest previous score.2.4Exploratory analyses of predictive factors for both symptom recurrence and the duration of triptorelin treatment were also conducted. For symptom recurrence, factors evaluated included age, body mass index, duration of medical attention, reproductive status, comorbidities, history of surgery, surgical procedures, the site and number of DIE lesions, pain prior to surgery, pain intensity, number of triptorelin doses, and concomitant medications after GnRHa. Predictive factors associated with treatment duration included age at surgery, DIE lesion, previous surgical diagnosis of endometriosis, previous hormonal treatment for endometriosis, history of pregnancy, intensity of dyspareunia, dysmenorrhea, menorrhagia, gastrointestinal, urinary, and pain symptoms prior to surgery and previously infertility.2.5All spontaneously reported adverse events were collected up to 1 month after the last triptorelin injection.2.6Baseline characteristics were assessed with descriptive statistical analysis; the mean ± standard deviation (SD) or median (range) are presented for continuous variables and frequency distribution  presented for categorical variables. Evolution of symptoms intensity scores and proportion (%) of patients are presented. Logistic regression was used to estimate the cumulative improvement and recurrence rates.P < .20) in the univariate analysis were entered in the multivariate model. All tests were 2 sided and a level of P < .05 was considered as statistically significant. All statistical analysis was performed in SAS version 9.21 .Univariate and multivariate binary logistic regression models controlling for baseline characteristics and numbers of triptorelin injections were used to assess risk factors for symptom recurrence. Univariate and multivariate Cox proportional regression models controlling for baseline demographics and clinical characteristics were used to identify factors associated with triptorelin treatment duration. The factors significant at 20%  patients with triptorelin-therapy following conservative surgery for DIE were included in the final analysis Fig. . FifteenThe baseline characteristics of patients are shown in Table During surgery, 149 (38.8%) patients displayed peritoneal superficial endometriosis and 357 (93.0%) had endometrioma. DIE lesions were located on the intestine, bilateral uterosacral ligament, vagina, ureter, and bladder in 55.5%, 50.5%, 9.6%, 2.6%, and 2.1% of patients, respectively. The majority of patients (64.8%) had a history of pregnancy. The proportion of history of miscarriage, voluntary abortion, therapeutic abortion, and ectopic abortions was 33.7%, 32.5%, 14.1%, and 3.2%, respectively.A total of 35 (9.1%) patients received 1 to 2 injections of triptorelin, 191 (49.7%) received 3 to 5 injections, and 158 (41.2%) received 6 injections. The median duration of drug exposure was 13.0 weeks (range: 0–29 weeks).3.2Changes in the intensity of symptoms over time from baseline (presurgery) to 24 months after surgery are summarized in Fig. At baseline, the proportions of women reporting pelvic pain, dysmenorrhea, ovulation pain, dyspareunia, or gastrointestinal symptoms were 58.1% 223/384), 84.1% (323/384), 35.9% (138/384), 42.4% (163/384), and 31.4% (119/379), respectively; at 24 months, these proportions were reduced to 16.0% (34/213), 23.0% (49/213), 6.6% (14/213), 5.6% (12/213), and 2.8% (6/213), respectively , metrorrhagia (9.6%), and urinary symptoms (7.6%) and the proportions decreased further from baseline to month 24 Fig. .Among patients with a symptom intensity score >0 at baseline, the cumulative improvement rates at 12 months were 72.6% for pelvic pain, 83.3% for dysmenorrhea, 55.1% for ovulatory pain, 66.9% for dyspareunia, 78.0% for menorrhagia, 59.5% for metrorrhagia, 75.6% for gastrointestinal symptoms, and 58.6% for urinary symptoms. Almost all improvements occurred in the first 12 months. Similar cumulative improvement rates were observed for all symptoms at 24 months  as the risk factors for symptom recurrence (Table P = .001) and in patients with moderate pain  or severe pain  compared with those with none or mild pain.The univariate logistic regression analysis identified DIE lesion in the intestine or in uterosacral ligament, presurgery pain symptoms with or without gastrointestinal symptoms and with or without infertility, number of DIE lesion locations, intensity of pain, and number of doses of triptorelin  were identified by the univariate Cox regression as predictive factors for triptorelin treatment duration (Table P = .044), who previously received hormonal treatment for endometriosis compared with those who did not , and shorter in patients who were infertile versus fertile .Age, associated DIE lesion, history of hormonal treatment for endometriosis, presurgery intensity of dysmenorrhea, ovulation pain, and gastrointestinal symptoms and infertility  adverse events were reported , which were similar to the previously reported 6-month dysmenorrhea recurrence rate of 13.3% following completion of 24 weeks of triptorelin treatment. Differences in study design and patient inclusion and exclusion criteria are likely to contribute to differences in symptom recurrence rates. The symptom recurrence rate gradually increased across follow up period, highlighting the importance of long-term healthcare in symptom management.In the present study, recurrence was evaluated based on symptoms of endometriosis. The overall 12-month cumulative rate of symptom recurrence was 12.8%, which was higher than the reported rate of 5% in a randomized study. Surgery is a common treatment option for patients with DIE. A previous report suggested that conservative surgery should be offered if the total excision of DIE foci is possible. Regarding the alleviation of pain, the benefits of surgery should always be balanced with the risk of intraoperative complications.,26 For previously infertile women with DIE, whether to opt for in vitro fertilization treatment or surgery first can be a dilemma. Pregnancy complications, such as placenta previa, gestational hypertonia, and intrauterine growth restriction have been shown to be more common in women with DIE even after complete excision compared with women without endometriosis.,28At present, there is no consensus regarding the treatment regimen for DIE, although a stepwise approach is usually suggested. Particular care and attention are required when managing these high-risk patients.Identifying risk factors for recurrence may assist early intervention and prevention. In addition to the multiple DIE locations and more severe pain symptoms identified as risk factors for recurrence in the present study, a positive family history has been shown to be a risk factor for endometrioma recurrence. However, as the study did not directly capture how many women tried to become pregnant during the 24 months follow-up, the interpretation of this observation is unclear. Furthermore, the present 24-month pregnancy rate for previously infertile patients was substantially lower than the 24-month pregnancy rate of 80% observed in previously infertile patients treated with triptorelin in the randomized controlled trial by Xue et al. A possible reason for this difference is the older age of patients in this study compared with the study by Xue et al , as the problem of infertility is greater and the planning of pregnancy less common in older patients.The overall 12-month and 24-month pregnancy rates in this study were 10.9% and 17.2%, respectively. For the subpopulation of previously infertile subjects, pregnancy rates were higher, with 18.6% at 12 months and 27.1% at 24 months. This 12-month pregnancy rate was slightly lower than that reported of 27.5% for previously infertile women with endometriosis treated with triptorelin in a randomized controlled trial (27.5%). demonstrated improvements in pelvic pain of patients with DIE with GnRH-a treatment, consistent with the present results, and also showed that the effect of GnRH-a was closely related to the treatment duration. In this study, the triptorelin treatment duration showed great variation across the study population. Most women received either 3 (30.0%) or 6 injections (39.6%). The Cox-regression model suggested that patients who were older at the time of surgery, fertile, or with history of hormonal treatment for endometriosis tended to be treated with triptorelin for longer. Thus, treatment duration is associated with patient health status, disease severity, and history of therapy.A recent randomized trial by Angioni et al,16,19,29The most common adverse effects in patients treated with triptorelin were menopause symptoms  in agreement with results from previous studies.The key strength is that it is the first real-world study focusing on the efficacy and safety of triptorelin treatment after surgery in patients with DIE in multiple centers in China. It reflects real-world clinical practice in China and may provide clinical guidance in the future. Additionally, risk factors of symptoms recurrence might help clinical decisions for prevention of recurrence.There are, however, several limitations. As a non-interventional study conducted in routine clinical practice, missing data are inevitable. Also, in the absence of a control group, the results of efficacy and safety can only be compared with published studies. In addition, the treatment regimen and duration were adjustable, according to routine clinical practice, which may have influenced the outcomes. Furthermore, due to the first follow-up visit was 3 months after surgery , it was difficult to determine the immediate effectiveness of surgery. Importantly, DIE has a complex phenotype and, as such, evaluation of symptom improvement alone may not capture the effects of treatment on all aspects of the disease.It can be concluded that triptorelin following conservative surgery for DIE had a beneficial impact on pelvic pain, dysmenorrhea, ovulation pain, and dyspareunia. Over 24 months, the recurrence rate of symptoms was low and triptorelin was generally well tolerated.The authors thank all patients involved in the study, as well as their caregivers, care team, investigators, and research staff in participating institutions. The authors also thank Beijing Preintell Biomed Co., Ltd., who provided medical writing support, which was sponsored by Ipsen, in accordance with Good Publication Practice guidelines. Furthermore, the authors gratefully acknowledge all the investigators of research institutions for their contribution to the study: Li Hong , Juxin Zhang , Min Hao , Jianliu Wang , Ouping Huang , Hongbo Wang , Jun Zhang , Dong Zhao , Weidong Zhao , Zhiqing Liang , Lifang Sun .Libo Zhu performed the study and was a major contributor in writing the manuscript. Zheng Guan, Yan Huang, Keqin Hua, Liguo Ma, Jian Zhang, and Dazhen Yang performed the study and made a contribution to the study design and manuscript draft. Valerie Perrot and Hongbo Li analyzed and interpreted clinical data, provided feedback on the manuscript. Xinmei Zhang designed and performed the study, was a major contributor in writing the manuscript and gave final approval of the version to be submitted. All authors read and approved the final manuscript.Conceptualization: Xinmei Zhang.Data curation: Zheng Guan, Yan Huang, Keqin Hua, Liguo Ma, Jian Zhang, Dazhen Yang, Xinmei Zhang.Formal analysis: Zheng Guan, Yan Huang, Keqin Hua, Liguo Ma, Jian Zhang, Dazhen Yang, Valerie Perrot, Hongbo Li.Funding acquisition: Xinmei Zhang.Investigation: Xinmei Zhang.Methodology: Libo Zhu, Zheng Guan, Yan Huang, Keqin Hua, Liguo Ma, Jian Zhang, Dazhen Yang, Xinmei Zhang.Project administration: Libo Zhu, Zheng Guan, Dazhen Yang.Resources: Libo Zhu, Xinmei Zhang.Software: Valerie Perrot, Hongbo Li.Supervision: Dazhen Yang, Hongbo Li, Xinmei Zhang.Validation: Valerie Perrot, Xinmei Zhang.Writing – original draft: Libo Zhu.Writing – review & editing: Zheng Guan, Yan Huang, Keqin Hua, Liguo Ma, Jian Zhang, Dazhen Yang, Xinmei Zhang.


Spinal cord stimulation (SCS) is an effective treatment in failed back surgery syndrome (FBSS). The effect of neuropathic pain medication use on SCS outcome is poorly understood.To study the effect of gabapentinoid use on SCS outcome measured by trial success, explantation rate and opioid dose reduction during a 2-yr follow-up.The study cohort included 203 consecutive FBSS patients who underwent SCS in a single tertiary center during January 1997 to March 2014. Purchase data of gabapentinoids, opioids, tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, and benzodiazepines during January 1995 to March 2016 were retrieved from national registries.P = .03). In contrast, patients with opioid use of >40 morphine milligram equivalent before implantation had significantly more explantations . In bivariate logistic regression analysis adjusted for patient specific factors, year of SCS implantation, use of neuropathic pain medication, opioids, and benzodiazepines, patients using gabapentinoids significantly more often discontinued opioids or reduced their dose by more than 50% during the 2-yr follow-up .In multivariate Cox regression analysis, patients using gabapentinoids had significantly fewer explantations during the 2-yr follow-up (hazard ratio [HR] 0.2, 95% CI 0.04-0.81, The use of gabapentinoids was associated with a significantly lower spinal cord stimulator explantation rate and a higher chance of opioid discontinuation or >50% dose reduction. This indicates that patients with SCS could benefit from concomitant use of gabapentinoids. Prospective randomized trials are warranted to verify this hypothesis. CDCCenters for Disease Control and PreventionDDDdefined daily doseFBSSfailed back surgery syndromeGABAgamma-aminobutyric acidIPGimplantable pulse generatorKUHKuopio University HospitalMMEmilligrams of morphine equivalentSCSspinal cord stimulationSNRIserotonin and noradrenaline reuptake inhibitorTCAtricyclic antidepressant1 The typical symptom is pain in the lower extremities and/or chronic back pain, leading to low health-related quality of life.2 Failure rates are 30% to 46% for lumbar fusion and 19% to 25% for discectomy.4 FBSS lacks curative treatment, and its complexity suggests a multidisciplinary team approach to optimize the outcome.Failed back surgery syndrome (FBSS) is a term used to describe patients with persistent pain after lumbar spinal surgery.5 Gabapentinoids prevent trafficking of the calcium channel complex to the plasma membrane via their binding to the α2δ subunit, which is functionally upregulated following nerve injury in animal models and may contribute to the development of hyperalgesia and allodynia.6 This indicates that voltage-gated calcium channels are a key pain target.7The pharmacological treatment of FBSS with a predominant neuropathic radicular component is based on gabapentinoids and antidepressants.8 It is a safe and cost-effective treatment for selected patients not responding to conventional pharmacological treatment for FBSS.9-11 In spinal cord stimulation (SCS), epidural electric stimulation to dorsal columns in the spinal cord elicits a sensation of paresthesia in the corresponding dermatomes.We present a retrospective analysis of gabapentinoid use among 203 consecutive FBSS patients treated with SCS in a single tertiary hospital during a 17-yr period. We studied the effect of gabapentinoid use on SCS outcomes measured by trial success, explantation rate, and opioid dose reduction in patients with continuous SCS use during a 2-yr follow-up. 000 person catchment population in Finland. The study group consists of all consecutive 211 patients  is a tertiary center solely providing full-time acute and elective neurosurgical services for the 850FBSS was defined as radicular leg pain with or without lumbar pain after one or several lumbar surgeries due to spinal stenosis or disc herniation. The diagnosis was made by a pain specialist, orthopedic surgeon, or neurosurgeon. Conservative treatment according to best practice was initiated, including oral analgesics and physical therapy. 565, Medtronic, Dublin, Ireland) was microsurgically implanted into the epidural space under direct visual control with the operating microscope under general anesthesia. The implantation techniques have previously been described.12The SCS paddle-lead electrode  was implanted after trial  in patients, who reported adequate pain relief and paresthesia, covering of most of the leg pain area. Global patient satisfaction instead of a formal percentage of pain relief was used as a criterion for permanent IPG implantation. All patients receiving an IPG had an outpatient clinic visit 2 to 4 mo (mean 105 d) postsurgery and when needed .Implantable pulse generator  or electrode type change (n = 4), and they were excluded from subsequent analyses . The Finnish Social Insurance Institution upholds a prospective registry consisting of prescribed medications, prescription dates, medication purchase dates, amounts, and prices of all prescription medications of citizens living in Finland. We studied the purchasing data for gabapentinoids, tricyclic antidepressants (TCA), opioids, serotonin and noradrenaline reuptake inhibitors (SNRI), and benzodiazepines. Nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from this study because approximately half of ibuprofein use, which is the most common NSAID in our country, consists of over-the-counter purchases.We calculated the total defined daily doses (DDD) for each medicine by multiplying the strength of each tablet by the total purchased package size and dividing the result by the DDD of the medication as defined by the WHO.13-17 For subsequent analyses, opioid users were divided into 2 groups: low-dose group with mean opioid use of <40 MME/day and high-dose group with mean opioid use of >40 MME/day.18Opioids included morphine, hydromorphone, oxycodone, codeine, fentanyl, dextropropoxyphene, buprenorphine, tramadol, and methadone. Their conversion ratios to milligrams of morphine equivalents (MMEs) were derived from the Centers for Disease Control and Prevention (CDC) as follows: 0.15 (codeine), 0.10 (tramadol), 75 (buprenorphine TD), 0.2 (dextropropoxyphene), 1.0 (morphine), 3.0 (methadone), 1.5 (oxycodone), 4.0 (hydromorphone), and 100 (fentanyl TD). The conversion factors for transdermal fentanyl and methadone are used by the Centers for Medicare & Medicaid Services with assumption that one patch delivers the dispensed micrograms per hour over a 24-h day, and 1 mg of parenteral fentanyl is equivalent to 100 mg of oral morphine.Benzodiazepines included diazepam, chlordiazepoxide, oxazepam, potassium clorazepate, lorazepam, clobazam, and alprazolam. Gabapentinoids included gabapentin and pregabalin. TCAs included amitriptyline and nortriptyline. SNRIs included venlafaxine and duloxetine.We studied the purchase data encompassing the 2 yr before and after SCS device implantation to have a complete history for all patients. Use of medication is defined as 2 or more purchases during the given period.A Cox regression survival analysis model was used to determine factors associated with explant for ineffective therapy. Results were presented as an adjusted multivariable model with the independent variables of gender, age, number of previous operations, duration of pain, location of pain, instrumented lumbar fusion (yes/no), year of SCS operation , use of benzodiazepines, use of opioids >40 MME/day, use of TCAs, use of SNRIs, and use of gabapentinoids.U test. Binary logistic regression analysis was used to compare trial success and opioid dose reduction with gender, age, number of previous operations, duration of pain, location of pain, status of instrumented lumbar fusion, year of SCS operation, use of benzodiazepines, use of opioids >40 MME/day, use of TCAs, use of SNRIs, and use of gabapentinoids as covariates. A linear mixed effect model was used to determine interactions with the following covariates: time , group, and time * group, with neuropathic pain medication use as the dependent variable. All 2-sided P-values < .05 were considered statistically significant.Categorical data have been presented as frequencies and proportions and assessed with chi-square or Fisher's exact tests as appropriate. Continuous data that were not normally distributed were assessed with the Mann-Whitney Study protocol was approved by the Institutional Review Board of KUH.Of the 203 patients included in the study, 76 (37%) were using gabapentinoids preoperatively, and of these, 26 (34%) were also using opioids over 40 MME/day. Of the 127 patients not using gabapentinoids preoperatively, 25 (20%) patients were using opioids over 40 MME/day. Gabapentinoids were combined with TCA in 20 (26%) patients, and SNRI in 18 (24%) patients. TCA alone was used in 21 (16%) patients, and SNRI alone in 14 (11%) patients. Following a 1-wk trial, the SCS electrode was removed in 47 patients . Gabapentinoid use was not associated with trial success (Table The mean use of gabapentinoids in the 6-mo period before implantation was 0.5 ± 0.7 (mean ± SD) DDD/day in the permanent SCS group, 0.3 ± 0.7 DDD/day in the SCS trial only group, and 0.3 ± 0.6 DDD/day in the explanted group Figure . No signOf the 156 patients with SCS devices implanted after trial, 44 (28%) were using gabapentinoids during the 2-yr follow-up, and of these, 11 (25%) were also using opioids over 40 MME/day. Of the 112 patients not using gabapentinoids during follow-up, 31 (28%) patients were using opioids over 40 MME/day. Gabapentinoids were combined with TCA in 10 (23%) patients, and with SNRI in 15 (34%) patients.P = .026). In contrast, patients with opioid use over 40 MME/day after implantation had significantly more explantations   Table . ExplantOf the 135 patients with SCS in use throughout the follow-up, 89 (66%) were using opioids before implantation, with a mean dose of 33 mg MME/day. Of these 89 patients, 29 (32%) were using gabapentinoids, and 37 (41%) were able to reduce opioid use >50% or discontinue opioids during the follow-up.P = .015). Patients using opioids over 40 MME/day before SCS implantation were significantly less often able to discontinue opioids or reduce their opioid dose >50%   on the McGill Pain Questionnaire.20 Duloxetine improved the affective component of pain 1 yr following surgery, as compared to patients with SCS alone. Neither the use of opioids nor neuropathic pain medications were associated with changes in the odds of a successful SCS trial or a 50% pain reduction.21 Quality of life after SCS was better with a combination of opioid and gabapentinoid therapy than with opioid therapy alone.22Gabapentinoid users were able to reduce their opioid dose significantly more often than nonusers. Effects of neuropathic pain medication on SCS outcomes have previously been analyzed in 3 studies , and excitatory neurotransmitters (glutamate and aspartate).25-27 SCS initiates neuropathic pain modulation through a supraspinal-spinal feedback loop and serotonergic descending fibers.28 The SCS effect on inhibitory pathways presents a possibility of augmenting pharmacological effects of stimulation.SCS seems to modulate pain from neurotransmitters, through neuroplasticity, to cortical and subcortical neurocircuits. Multiple studies show that SCS attenuates wide dynamic range spinal interneuron hyperexcitability through Aβ-mediated inhibitory control.23 and when studied at a cellular level, a wide dynamic range of neurons showed prominent hyperexcitability. GABAB receptor agonist baclofen, when administered intrathecally, has shown a prominent effect of potentiating the pain suppression effect of SCS in both humans and rodents.29 A subeffective dose of amitriptyline enhanced the suppressive effect of SCS on mechanical hypersensitivity.30 However, among 19 patients using amitriptyline in our study, no significant effects on either opioid dose reduction or SCS explantation rate were observed.Our results are in line with previous rodent studies, suggesting that gabapentinoids might have a beneficial effect on SCS that cannot be observed with gabapentinoids alone. Subeffective doses of gabapentinoids combined with SCS significantly attenuated allodynia,This was a retrospective study with obvious limitations. Patients who are reliant on gabapentinoid therapy may have different pain pathology (neuropathic) than patients who are more reliant on opioid therapy (nociceptive). In our hospital, SCS is implanted only for neuropathic pain, which is diagnosed by an experienced pain physician and/or neurosurgeon with neuromodulation expertise. Leg pain in FBSS is most likely radicular neuropathic pain, whereas back pain is more often nociceptive. However, in multivariate analyses, pain location was not a significant risk factor for SCS explantation or opioid dose reduction.32 Moreover, subjective pain questionnaires are not always ideal for analyzing pain with fluctuating characteristics. Psychological, emotional, and functional limitations that change over time may affect the subjective pain perception and reporting.33We have used hard endpoints, trial success, explantation rates, and opioid dose reduction to determine the SCS outcome. This approach has been used previously in registry-based studies.Medication use was based on nation-wide registry data and is considered more reliable than patient's own report of use, which is more likely to be influenced by the patient-doctor relationship. Pregabalin was not accepted as a licensed medication in Finland before 2004, which affects the total amount of medication used during the study period. Gabapentin was licensed throughout the study. This has been controlled in the multivariate analyses with a time covariate; overall explant rates did not differ before and after 2004. Pregabalin was protected under patent and expensive throughout the study, and we presume that patients with repeated purchases have complied with the medication regiment.34We have studied a well-characterized and homogenous cohort of patients with FBSS. The findings may not be generalizable to other patient groups, including complex regional pain syndrome, where inflammation plays an important role.35 This needs to be further studied, preferably in a randomized controlled setting.In our study, all implantations were made with a surgical paddle lead with tonic stimulation, which was the only waveform used at that time in our practice. Gabapentinoid effect could be different in paresthesia-free stimulation with partially different pain pathways and possibly different pain transmitting cytokines.The use of gabapentinoids was associated with a lower spinal cord stimulator explantation rate and a higher chance of over 50% opioid reduction. This indicates that patients with SCS may benefit from concomitant use of gabapentinoids. Prospective randomized trials would be warranted to verify this hypothesis.This study is supported by Medtronic, State Research Funding of Kuopio University Hospital, and University of Eastern Finland. All authors are affiliated with the Kuopio University Hospital or University of Eastern Finland.Dr Nissen, Ms Ikäheimo, Dr Huttunen, Dr Jyrkkänen, and Dr von und zu Fraunberg have received travel funding from Medtronic. The other author has no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Dr Nissen has also received funding from Finnish Association for the Study of Pain and travel funding from Boston Scientific and Abbott St Jude Medical. Ms Ikäheimo, Dr Huttunen, Dr Jyrkkänen, and Dr von und zu Fraunberg have received travel funding from Abbott St Jude Medical.


The early and late periods featured similar pain outcomes. The operation time correlated with the total periods with a correlation coefficient of 0.271 (p < 0.001). In conclusion, the postoperative pain following whole third molar extraction was related to the operation time rather than the anesthetic methods.This study examined the effects of general anesthesia on the postoperative pain level after third molar extractions compared to local anesthesia. This retrospective study included patients who underwent four simultaneous third molar extractions under general or local anesthesia and had records of their postoperative pain levels . The pain level was determined in the early  and late (POD #3-7) periods. The operation time and recently modified difficulty index were analyzed to validate the homogenous condition of the extraction. Of the 227 male inpatients (aged 20.9 ± 1.3 years), 172 and 55 patients underwent third molar extractions under local and general anesthesia, respectively. The age and difficulty index were distributed equally, but the operation time was longer in general anesthesia than in local anesthesia ( Of all dental procedures, third molar extraction causes the highest level of patient anxiety ,2,3. AftGeneral anesthesia is performed in patients who feel severe anxiety about dental treatment or suffer from the vomiting reflex or when surgery is required in a region adjacent to an anatomically dangerous structure. Furthermore, it was reported that dental surgery performed under general anesthesia minimizes anxiety and gives great satisfaction to the patients ,9,10. ThNevertheless, general anesthesia should be considered the last treatment option because it carries a relatively high risk to the overall health, opportunity costs, and time spent preparing the anesthesia . RegardiRecent studies have suggested the modified difficulty indices according to the spatial relationship, which was subcategorized based on the angle between the long axis of the third molar and the adjacent second molar ,13. In 2The authors hypothesized that the anesthetic methods do not affect postoperative pain after extraction surgery. This study analyzed the effects of general anesthesia on the postoperative pain level after whole third molar extraction compared to local anesthesia.The Institutional Review Board at the Armed Forces Capital Hospital approved this retrospective study (AFCH-20-IRB-034). The study was conducted according to the principles of the Declaration of Helsinki for research on humans. All the patients included in this study were adult inpatients who underwent four third molar extractions on both sides from January 2013 to November 2017 and had records on the postoperative pain levels of patients.The inclusion criteria were as follows: (1) inpatients aged 19–24 years; (2) extraction of whole impacted third molars (both upper and lower third molars) at once under general or local anesthesia in the operating room; (3) informed consent from voluntary participants. The exclusion criteria were as follows: (1) uncontrolled systemic disease or dentofacial syndrome; (2) untreated dental caries or periodontitis; (3) related pathologic conditions, such as odontogenic cyst or pericoronitis; (4) heavy smoker (≥12 cigarettes per day).® Base Primea; Fresenius Kabi, Bad Homburg vor der Höhe, Germany), 60 mg lidocaine, 160 mg propofol, and 50 mg rocuronium. The patient’s trachea was intubated with a nasal endotracheal tube  with an inner diameter of 7.0 mm. Oxygen and air were supplied at a fraction of inspired (FiO2) oxygen of 0.5 with sevoflurane. During anesthetic maintenance, the sevoflurane concentration was controlled so that the blood pressure and heart rate were held within 20% of the preoperative measurements; remifentanil was injected continuously for analgesia where necessary. Additional local anesthesia with 2–4 7.2 mL lidocaine ampules was also infiltrated on the buccal vestibule and the palatal or lingual mucosa of the impacted third molars. After surgery, sevoflurane and air were discontinued. In the immediate postoperative period, ketorolac was injected as a rescue analgesic. Pyridostigmine and glycopyrrolate were injected to reverse muscle relaxation when the patient could breathe spontaneously and respond to verbal commands.Each patient was transported to the operating room without premedication with antibiotics and monitored with a non-invasive blood pressure monitor, a pulse oximeter, and a three-channel electrocardiograph. Local anesthesia involved infiltrating from five to eight 7.2 mL ampules of 2% lidocaine HCl  on the buccal vestibule and the palatal or lingual mucosa of the impacted third molars. General anesthesia was induced by an intravenous injection of remifentanil using a TCI system  was packed to prevent food packing and bleeding. The patients were instructed to take oral antibiotics  and NSAIDs  three times daily for five days and a daily mouth rinse with a chlorhexidine solution.Three expert oral and maxillofacial surgeons (extraction experience ≥ six years) performed the surgery. After exposing the mandibular third molar with or without an additional mesial or distal incision, an odontotomy was performed using a 2.0-mm round burr with a RemB straight microdrill . After curettage of the remaining granulation tissue, a collagen plug . The VAS from the day of surgery  to the seventh day (POD #7 day) was investigated at 7 PM after dinner by a nurse. The maximum pain level was determined in the early (POD < #3) and late (POD #3–7) periods.t-test. The operation time was defined as the time from the start of the incision to the last suture. Briefly, the difficulty scores for the mandibular third molars were defined considering the spatial relationship (1–5 points), depth (1–4 points), and ramus relationship (1–3 points) using cone-beam computed tomography .According to the anesthetic methods, the difficulty indices were analyzed using Pearson chi-squared test. The age, operation time, and VAS were analyzed using an independent p < 0.001), but the difficulty index was similarly distributed between the anesthetic methods . Under general anesthesia, the operation time was longer (44.07 ± 19.09 min) than under local anesthesia  and late  periods .p < 0.05). In particular, the operation time and the total period of pain correlated with a correlation coefficient of 0.271 . The postoperative pain was most related to the sum of pain during the entire follow-up period with a correlation coefficient of 0.271 (p < 0.001). This result was in accordance with the previous research showing that prolonged operation time could increase postoperative complications [Although the pain score did not show a difference between the anesthetic methods, this study analyzed the relationship between the difficulty index and operation time regarding other factors contributing to postoperative pain. The difficulty index did not have any significant effect on postoperative pain. On the other hand, pain correlated with the operation time in all the periods (ications ,24,25,26Various factors can affect the operation time, such as tooth anatomy, the patient’s position, various surgical methods, and the surgeon’s condition and experience. Although validation of the difficulty index has been reported in a recent study , the opeThis retrospective study had several limitations, such as a heterogeneous extraction process, comparison with outpatients, and absence of subjective satisfaction, including the postoperative pain, masticatory function. In this study, the straight air drill used in the operation room had a higher torque than the low-speed handpiece and a different access entrance to the surgical field from the high-speed handpiece at the dental chair. Further prospective research will be needed to reveal the relationship between the operation time and postoperative pain and the difference between the extraction in an operating room and the outpatient chairside with controlled incision design and subjective satisfaction.General anesthesia could not reduce the postoperative pain after the extraction surgery of an impacted third molar. On the other hand, prolonged operation time could be related to the degree of postoperative pain.


Background: The prevalence of musculoskeletal disorders (MSD) and vitamin D insufficiency is high. Past research indicating vitamin D supplementation and physiotherapy are useful for the treatment of MSDs. However, to the best of our knowledge, the combined benefits of vitamin D and physiotherapy are not yet evaluated in MSD. We hypothesized that combined intervention of vitamin D supplementation and physiotherapy would be more effective in relieving the pain of MSD compared to only physiotherapy intervention.Objective: This study aimed to examine whether combined effect of vitamin D supplementation and physiotherapy was better than physiotherapy alone in reducing pain-related outcomes  in patients with MSD.Methods: A quasi-clinical experiment was conducted between May 2020 and April 2021. Vitamin D level in the blood was measured at the start of the study. Patients with vitamin D levels <20 ng/mL were assigned to the combined physiotherapy and vitamin D group. The physiotherapy group consisted of the patients with vitamin D levels more than 20 ng/mL. The Brief Pain Inventory scale was utilized to measure pain at baseline and after 12 weeks of interventions. We used the paired t-tests for unadjusted analysis. Further, a linear regression model was used to identify the combined effect of physiotherapy and vitamin D on reducing pain scores after adjusting potential confounders.Results: Combined intervention of vitamin D and physiotherapy showed significantly better results than only physiotherapy intervention in the reduction of three pain-related outcomes (p < 0.001). The multivariable analysis indicated that the combination of physiotherapy and vitamin D treatment reduced pain score by 1.126  compared to physiotherapy alone.Conclusion: Combined intervention (vitamin D with physiotherapy) had a better pain-relieving effect than physiotherapy alone. To confirm these findings, more research is needed with randomized control trials.Clinical Trial Registration: [http://ctri.nic.in/Clinicaltrials/advancesearchmain.php], identifier [CTRI/2020/04/024845]. According to the Global Burden of Disease study 2019, 1.7 billion people worldwide exhibit musculoskeletal disorders (MSD), which is the leading cause of disability  D) (vitamin D) deficiency. Vitamin D deficiency affects 24% Americans, 37% Canadians, and 40% Europeans; in India, 490 million people exhibit vitamin D deficiency .A positive association between vitamin D deficiency and the leading MSD, such as LBP, neck pain, and knee pain, among others has been indicated. A triple-arm controlled study suggested that severe vitamin D deficiency is associated with sub-acute and chronic LBP . A systeDespite having a variety of options, managing MSD can be difficult and expensive; nonetheless, the results of any given treatment are not always adequate and are not recommended for universal usage , 14. SupPatients with musculoskeletal pain  aged 24–80 years who sought physiotherapy treatment at the physiotherapy and rehabilitation departments of Uttara Adhunik Medical College and Hospital in Dhaka and Hasna Hena Pain and Physiotherapy and Public Health Research Center in Dhaka city were randomly selected for this study. Patients under the age of 18 years and those who were experiencing pain because of cancer or tuberculosis were excluded from the study. Patients who did not adhere to the treatment plan or who desired to withdraw from the research were also excluded. Two hundred patients were eligible for the study based on the inclusion and exclusion criteria. We approached 150 people to ask whether they wanted to participate in the study, and 143 of them agreed. Eight patients later dropped out of the research. After 12-weeks, 135 patients finally gave data for the study. The flow chart has been presented in This was a clinical trial using a quasi-experimental design. Data were collected at baseline and 12 weeks after the intervention between May 2020 and April 2021. Participants who gave their consent and met the inclusion criteria were interviewed using the Brief Pain Inventory (BPI) scale to record pain levels at baseline and after 12 weeks of pain relief intervention. Patients were also examined for vitamin D, hemoglobin, and nutrition levels. Following a standard protocol, a blood sample was collected from patients at the Uttara Adhunik Medical College and Hospital's Department of Pathology and Biochemistry.The pain severity subscale of BPI was used to measure self-reported overall pain severity. The pain severity subscale consists of four items that inquire for worst, least, and average pain intensity ratings within the last 24-h in addition to present pain ratings. Pain intensity is rated using an 11-point numerical rating scale in which 0 indicates “no pain” and 10 indicates “pain as bad as you can imagine.” An overall pain severity rating is calculated as a mean of the four items on pain intensity. The BPI is an internally consistent , reliable, and valid measure of pain severity and pain interference for people with musculoskeletal pain .The BPI pain interference subscale consists of seven items that assess the extent to which pain interferes with the mood, relations with other people, and enjoyment of life . ResponsConsistent with previous work, the physical interference subscale was calculated from BPI scale items relating to how pain interferes with a person's engagement in general activity, walking, and normal work-related activities . The thrThe physical and affective factor's items of BPI are supported by confirmatory factor and Rasch analysis , 20. PaiMini Nutritional Assessment-Long Form, individuals can be divided into three groups using threshold values of <17 for “malnourished,” 17–23.5 for “at risk of malnutrition,” and ≥24 for “normal nutritional status,” with a maximum total score of 30 points D was used to evaluate the vitamin D status among the study participants. The laboratory analysis was conducted at the Department of Biochemistry, Uttara Adhunik Medical College and Hospital. The serum concentration of 25(OH)D was measured by chemiluminescence microparticle immunoassay . Patients were classified based on vitamin D levels as deficient (<20 ng/mL); insufficient 20–30 ng/mL); and sufficient (>30–100 ng/mL) , 30. ng/mL; aA hematology analyzer  was used to estimate the concentration of hemoglobin in the blood. Patients with hemoglobin levels between the ranges of 13–18 g/dL were considered normal.The participants were distributed into two groups according to their vitamin D levels: physiotherapy and physiotherapy + vitamin D groups. The physiotherapy group consisted of patients who had vitamin D levels ≥ 20 ng/mL. Rest of the patients (vitamin D level < 20 ng/mL) were included in the physiotherapy + vitamin D group. All the patients were given traditional physiotherapy interventions for a maximum of 21 sessions. However, only the physiotherapy + vitamin D group was given a 40,000 IU vitamin D3 capsule made by a specific pharmaceutical company of Bangladesh per week for 8 weeks. To ensure the correct dose, patients were asked to visit the Uttara Adhunik Medical College and Hospital or Hasna Hena Pain and Physiotherapy and Public Health Research Center to take the capsule on full stomach at afternoon every week. A card with a chart of capsule-taking dates was maintaining to avoid any misconduct. Although there are no reported adverse effects of physiotherapy and vitamin D supplementation, the contact number of a physiotherapist and physician were given to the participants in case of any emergency or concern. Data were collected at the baseline and after 12 weeks.http://ctri.nic.in/Clinicaltrials/advancesearchmain.php. All participants provided written consent.The study was conducted following the ethical standards outlined in the Helsinki Declaration (1983). The Ethics Review Committee of Uttara Adhunik Medical College and Hospital approved the study. This clinical trial was registered prospectively from World Health Organization endorsed Clinical Trials Registry CTRI/2020/04/024845, Registered on 24/04/2020, t-test. The results were assessed using a 95% confidence interval. Finally, after adjusting for sex and age group, a multivariable linear regression model was conducted to examine the combined effect of vitamin D and physiotherapy on change in pain scores.The acquired data were entered into the IBM SPSS 21 program , and the statistical analysis was completed with R 3.6.3. The arithmetic mean and standard deviation (SD) were used to describe the continuous variables. Frequency and percentage were used to express categorical variables. For categorical variables, the chi-square and Fisher's exact tests were employed to determine the difference between the groups. Before and after the evaluation, the within-group comparisons were determined using a paired samples p = 0.569), age (p = 0.065), body mass index (p = 0.125), exercise habit (p = 0.363), diabetes mellitus (p = 0.877), hypertension (p = 0.130), hemoglobin level (p =0.879), nutrition level (p = 0.537), main complaints (p = 0.166), and pain duration (p = 0.811).This quasi-experimental study included 143 patients . p = 0.001), affective interference score (p = 0.001), and physical interference score (p = 0.001).The descriptive results of changes in pain scores between before and after interventions are shown in p = 0.035).The findings of a multivariable linear regression model adjusted for sex and age are presented in The study shows irrespective of all measured potential confounders, vitamin D3 supplementation in addition to physiotherapy was significantly effective in reduction of pain severity and affective and physical interface. This novel finding provides a scientific basis on the role of vitamin D in improving musculoskeletal pain outcomes.To the best of our knowledge, we provide here the first quasi-experimental data of patients with musculoskeletal pain examining the effect of vitamin D supplementation in addition to physiotherapy compared to only physiotherapy intervention on the reduction of pain parameters . In line with our findings, a systematic review and meta-analysis of published randomized controlled trials suggested that vitamin D supplementation can decrease pain scores significantly . AnotherOur study suggested that the patients with LBP, neck pain, shoulder pain, and knee pain were equally benefited from vitamin D supplementation along with physiotherapy. Managing one of the major global burdens, that is, LBP is a significant challenge for the clinicians . Our stuA systematic review has revealed the beneficial effect of vitamin D supplementation when treating neck pain . SimilarThe association between hypovitaminosis D and poor health outcome is well-known; however, the relationship between vitamin D and chronic pain is not clear yet. Furthermore, the mechanism by which vitamin D inhibits chronic pain development is still ambiguous. In light of the current lack of evidence, supplementation of vitamin D cannot be recommended as an effective independent treatment for chronic pain . HoweverThe strength of the study includes (1) sufficient number of patients recruited for both the vitamin D + physiotherapy and physiotherapy groups; (2) equal distribution of patients for each sub-group, for example, sex, age group, chief complaints, and pain duration; and (3) the standardized collection of data and pathological tests from a single research center.There were three limitations of this study. First, our study's quasi-experimental methodology was less reliable than a randomized controlled trial. Second, we included patients with the combination of vitamin D and physiotherapy treatment for vitamin D deficient patients, which may have influenced the pain score. Third, because of cost constraints, vitamin D concentration from blood was not tested after 12 weeks of intervention in this study.In conclusion, this study gives information on the future possible use of vitamin D supplementation in the treatment of patients with MSD when used in conjunction with physiotherapy. Combined intervention (vitamin D with physiotherapy) showed significantly better results than only physiotherapy intervention in the reduction of three pain-related outcomes, pain severity, affective interference, and physical interference, in musculoskeletal pain. To confirm these findings, more research is needed, including randomized controlled trials with placebo controls and longer follow-ups.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethical Review Committee (ERC) of Uttara Adhunik Medical College and Hospital. The patients/participants provided their written informed consent to participate in this study.MA conceived the idea, designed and conducted the trial, managed the project and participants, interpreted the data, drafted, and review the manuscript. ZU and AH supervised the study and review the manuscript. MA and AH performed the statistical analysis. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.