Pulsed radiofrequency (PRF) treatment on the dorsal root ganglion (DRG) has been proposed as a good option for the treatment of persistent radicular pain based on its effect of neuromodulation on neuropathic pain. Autologous conditioned serum (ACS) therapy is a conservative treatment based on the patient’s own blood. The aim of this manuscript is to develop a study protocol using ACS on the DRG as a target for its molecular modulation.We plan to conduct a randomized controlled study to compare the efficacy of PRF therapy plus ACS versus PRF therapy plus physiological saline 0.9% (PhS) on the DRG to reduce neuropathic pain in patients with persistent lower limb radiculalgia (LLR) and to contribute to the functional improvement and quality of life of these patients.Study participants will include patients who meet study the inclusion/exclusion criteria. Eligible patients will be randomized in a 1:1 ratio to one of treatment with PRF plus ACS  or PRF plus PhS (placebo group). The study group will consist of 70 patients (35 per group) who have experienced radicular pain symptoms for ≥ 6 months’ duration who have failed to respond to any therapy. Both groups will receive PRF on the DRG treatment before the injection of the sample (control or placebo). Patient assessments will occur at baseline, 1 month, 3 months, 6 months, and 12 months after therapy.The primary efficacy outcome measure is Numeric Pain Rating Scale (NPRS) responders from baseline to 12 months of follow-up using validated minimal important change (MIC) thresholds. A reduction of ≥ 2 points in NPRS is considered a clinically significant pain relief.The secondary efficacy outcome measure is the proportion of Oswestry Low Back Pain Disability Scale (ODS) responders from baseline to 12 months of follow-up in the experimental group (PRF plus ACS) versus the placebo group (PRF plus PhS). ODS responders are defined as those patients achieving the validated MIC of ≥ 10-point improvement in ODS from baseline to 12 months of follow-up as a clinically significant efficacy threshold.This prospective, double-blind, randomized placebo-controlled study will provide level I evidence of the safety and effectiveness of ACS on neuropathic symptoms in LLR patients.EUDRACT number: 2021–005124-38. Validation date: 13 November 2021. Protocol version {3}: This manuscript presents the 2nd protocol version.The online version contains supplementary material available at 10.1186/s13063-023-07787-y. Radicular pain is defined as pain perceived in an extremity or trunk wall caused by the activation of nociceptive afferent fibers from a spinal nerve  . Due to Lower limb radiculalgia (LLR) has an annual prevalence in the general population of 9.9% to 25%, which means that radicular pain is probably the most common form of neuropathic pain , 5. LLR Despite the availability of many treatments for LLR, the currently available evidence is insufficient for optimal therapy . ConservThe persistence of pain requires a neuro-histological and neuro-molecular consideration in order to find the adequate treatment targets. This is the reason why DRG is focused as a target for neuromodulation. DRG plays a key role in developing and maintaining radicular pain and its link to sensory disturbances. Apart from the neuron’s electrical potentials, the glia will drive an immune cascade of inflammatory mediators leading to peripheral and central sensitization. In addition, the hyperexcitability in afferent fibers is associated with changes in gene expression, in the ion channels themselves, leading to discharges, spontaneous bursts, which are the electrophysiological signature of neuropathic pain –18.PRF therapy on the DRG has been proposed as a good option for the treatment of persistent radicular pain based on its power of neuromodulation on neuropathic pain , 19–30. In order to be able to offer effective treatments for LLR, it is necessary open the field of research towards the cellular and molecular changes induced on the DRG. ACS therapy is a conservative treatment based on the patient’s own blood. A simple sample is taken from the patient, incubated and separated using a special device to produce a serum that is high in anti-inflammatory cytokines and growth factors. This serum is injected back into the patient in a series of 2 to 3 doses.Described in multiple clinical trials, ACS therapy reduces pain and improves function, mobility, and quality of life. Patients are treated safely without too many clinically relevant side effects. None of their rival treatments such as corticosteroid, hyaluronic acid, or platelet recombinant plasma (PRP) are unrivaled in terms of the duration of their effectiveness in reducing pain –37. WhenFor all these reasons, in this study, it is proposed not only to treat patients with radicular pain from a neuromodulatory therapy with PRF but also to add an autologous molecular therapy for the optimization and duration of the clinical improvement of neuropathic radicular pain. In this way, it is intended to treat the DRG electromagnetically and neurochemically in order to achieve the modulation and total reversal of the neuronal malfunction that comprises neuropathic pain {6b}.The primary objective of the RADISAC study is to measure the effectiveness of the PRF therapy plus ACS on the DRG neuropathic pain in patients with persistent LLR.The secondary objective is to evaluate the functionality, the quality of life, and the mood of patients during the first year after the treatment.This is a prospective, double-blind, randomized placebo-controlled trial designed to assess whether therapy with PRF + ACS on the DRG compared to PRF + PhS reduces neuropathic pain and its consequences, in patients with persistent LLR {8}.In addition, this it to evaluate if the fact of adding ACS can give a greater advantage for the reduction of pain in these patients.Taking into account that pulsed RDF is currently the interventional treatment with the best results to offer to patients with persistent chronic radiculalgia, it is the design of the study proposed to perform PRF therapy on the DRG for 8 min, 45 V of the root affected to all the patients included in the study. At the end of the PRF therapy, a 3-mL dose of ACS will be administered on the DRG to the patients of the experimental group and a 3-mL dose of 0.9% PhS will be administrated on the DRG to patients of the placebo group.A schematic patient flow diagram is presented in Fig. The project will be carried out in the facilities of the pain unit of Department of Anaesthesiology, Resuscitation and Pain Treatment at the Dexeus University Hospital (DUH) in Barcelona. The principal investigator is the first responsible of all the project and its development.The study population proposed is 70 patients over 18 years of age, not illiterate, with radicular pain in the lower limb for more than 6 months. In addition, the symptomatic diagnosis screening criteria to confirm LLR will be used prior to the patient enrolment in the study. The inclusion and exclusion criteria are shown in Table Both the main investigator and the other doctors of the pain unit will proceed to recruit patients within their usual clinical practice and according to inclusion and exclusion criteria {15}.All the candidates will be informed in detail of the following information: the purpose of the study, interventions, benefits, possible risks, and corresponding responses. The patient accepts by signing the informed consent (IC) that he/she voluntarily participates in the study accepting that he/she may belong to the placebo or experimental group. They will sign the informed consent form voluntarily and will have the right to withdraw from the study at any time without any risk. The IC also includes a specific section on privacy consent and protection of personal data, according to the legal framework {26a} {26b} {6b}.Randomization will be carried out using a simple randomization based on an equiprobable algorithm. According to randomization algorithm, a three-digit numerical code list will be generated with the R statistical software. It contains the three-digit and the assignation group. This list will be given to the laboratory and to the pharmacy service of the DUH, so only these both will know which of the groups is placebo and which of the groups is experimental. Only the part of the lists containing the 70 three-digit numerical code (not the assignation group) will be given to the main investigator. For each recruited patient, the main investigator will assign consecutively a three-digit code number and give to the patient a document with his name and the three-digit numerical code. When the patient will go to the laboratory, it will know if the patient belongs to the experimental group or the placebo group and proceed to prepare the samples. The principal investigator and the patients will be blinded for the remaining.To comply with double-blind blinding, the following steps will be followed for the extraction and preparation of the ACS:All patients will be scheduled 4 days before infiltration in the laboratory for blood collection and sample processing. Prior to extraction, patients will undergo the determinations based on the following documents: AEMPS REPORT/V1/23052013 and ROYAL DECREE 1088/2005. Given the laboratory will already know if the patient belongs to the experimental or placebo group, it will proceed to draw blood for the preparation of the ACS or not and store the syringes in the refrigerator at a temperature not exceeding – 18 °C.All patients will undergo a blood draw for the preparation, or not, of the ACS, so they will not be able to know at any time which group they belong to. The syringes with the ACS or PhS samples are identical and sealed so that the main investigator will not be able to know to which group the patient belongs to. In addition, the way to evaluate the improvement or not of the pain will be through the self-assessment tests that the patient will answer individually at the control visits with what the main investigator will transcribe the results of the tests to the study database.The day scheduled for infiltration, before performing the technique, adequate positioning of the patient, and proper monitoring in accordance with the protocol of the pain unit is mandatory. To perform the procedure, a transforaminal DRG approach technique will be performed under asepsis and antisepsis and under fluoroscopic vision. After checking the impedances (not higher than 450 ohms), the presence of sensory stimulation will be checked with a stimulation between 0.3 and 0.6 V and motor stimulation with a voltage at most double that is necessary to cause paresthesia. Finally, and once the injection of contrast is verified, PRF therapy will be carried out on the DRG . Once the therapy is finished, the sample assigned to the patient will be injected.Since most studies and clinical trials describe ACS therapy with 2 or 3 injections –37, sepaTime schedule of enrolment, interventions, assessments, and visits for participants is shown in Table The primary outcome will be level pain using Numeric Pain Rating Scale (NPRS). The NPRS is a segmented numeric version of the visual analog scale (VAS) in which a respondent selects a whole number (0–10 integers) that best reflects the intensity of his/her pain. A reduction of ≥ 2 points in NPRS is considered clinically significant pain relief . This ouEscala de Valoración del Estado de Ánimo (EVEA)]  , Quality (EVEA)] –47, and 4) scale , 49. TheThe total duration of the randomized placebo-controlled study is expected to be 36 months, including 24 months for patient recruitment and 12 months for final patient follow-up.At baseline, patient demographics and prior failed therapies will be documented, including frequency, duration, type, and compliance, as well as magnetic resonance imagining (MRI) and electromyography (EMG) diagnostic tests. Documentation of analgesic use for the treatment of LLR will include frequency, dosage, and duration. All baseline and post-procedural follow-up points will include reported outcomes documented through completing the NPRS, ODS, MOAS, SF-12, and DN4 questionnaires and documentation of narcotic and non-narcotic analgesic medication usage. Device and procedure-related adverse events and all serious adverse events will be documented throughout the study period Table .The data collected will be stored in locked cabinets, and only the main researcher will have access to this information. Data will be recruited in a computer spreadsheet with password protection to ensure confidentiality. To ensure no error, the spreadsheet will be monthly monitored and audited by a researcher who is blind to the participants’ group allocation and has no conflict of interest.All patients who leave the study for any reason will no longer have their data collected.The primary safety endpoint is the incidence of device- and/or procedure-related adverse events, which will be compared statistically between the randomized groups using proportions of patients experiencing such an event. The endpoint will be met if this event rate is not significantly greater with ACS than with PhS. All study-related adverse events will be monitored and reported, including seriousness, severity, treatment, and relationship to the study device/procedure. Adverse events collected in this study will be determined by the mine investigator to be specifically related to the products or procedures used in the 2 treatment groups or one that is determined to be a serious adverse event {22}.To date, all published studies with ACS have shown high safety rates and no side effects for what ACS product itself represents. Even so, any intervention can lead to an adverse effect, so their monitoring will be an essential condition in this protocol {11b}.Once the study has started, given that the inclusion of patients will be progressive over time as they are recruited, just in case there is a worsening of pain of more than 25% in more than 50% of the patients, the study would be reconsidered and the recruitment would be stopped to analyze the data and check if the worsening is in patients whom the ACS therapy was applied. If this were the case, the study would be definitively stopped and a report would be given to the laboratory. The author responsible for the study will carry out this audit if necessary. The main investigator together with the rest of the authors will make the decision to terminate the trial early {17b} {21a}.Any other adverse effect as far as the interventions are concerned will be collected and analyzed  {11b} {21b}.The main investigator is the only person who will be in charge of follow-up with clinical interviews at 30 days, 3 months, 6 months, and 12 months. A schedule of visits will be established for each patient for their greater adherence to the study and not to delay follow-up. Apart from the following-up visit controls, the patients will provide from a telephone number of pain unit for any doubts, changing pain characteristics, or new interventions they will receive. In that way, it provides an improving of adherence to protocol of the study {11c}.As far as the samples are concerned, both the laboratory responsible for the ACS and the pharmacy of DUH will have a record of the samples and their transport and temperature. Each sample will have a special label  and will be guarded by the pharmacy upon arrival from the laboratory and when it is withdrawn by the investigator on the day of its use for injection.The study will be carried out in the facilities of the DUH, a document of suitability of the facilities signed by the head of the Department of Anaesthesiology and pain unit. In the same way, a commitment document is attached by the Hospital’s Pharmacy Department for the control and monitoring of the study. The main investigator will take the responsibility to monitoring of the study. She will coordinate with the people in the laboratory, pharmacy, and pain unit. There is also a thesis director who will meet monthly with the author responsible for the study and running the trial day-to-day to provide organizational support. In conclusion, since the day-to-day task falls on the main investigator, she will be responsible for any important protocol modification and technical aspects of the trial as well as data collection, outcome analyses, and results. She will be in charge of notifying the rest of authors as well as laboratory and pharmacy {5d} {21a} {25}.Based on the existing bibliography in relation to the treatment of pain by ACS treatment for other similar affections , it is eA descriptive analysis will be carried out for all the data collected. The normality of the data will be studied using the Kolmogorov–Smirnov and Shapiro–Wilk tests. For continuous quantitative variables, descriptions of central tendency and dispersion will be presented: mean and standard deviation respectively in case the variables follow a normal distribution or median and interquartile range for those variables that are not normally distributed. For categorical  variables, frequencies and percentages will be presented. The main outcome (improvement > 2 points) will be tested using a generalized linear mixed model (GLMM). The GLMM model fit will include a between-subject factor and will also include a random effect for the time  and the interaction between group and time variables. The inclusion of the interaction terms allows for a formal test between the groups over time. For the other variables, the mean effects of the interventions and the differences between groups and their respective 95% confidence intervals will be calculated using regression linear mixed models for repeated measures, which will incorporate terms for the treatment groups, time, and interaction terms. Treatment coefficients versus time interactions will be equivalent to the estimates of the differences between groups. All models will be adjusted for chance imbalances in outcome between groups at baseline. There will also be analyses of the covariates collected, including age, gender, and duration of symptoms. The analyses will follow the principles of intention to treat, and no interim analyses will be performed. No additional analysis will be performed. If a patient drops out of treatment, no additional outcome will be collected. The significance level will be set at 5%, and SPSS for Windows will be used for the statistical analysis.The number of participants who complete the 12-month follow-up will be described by allocation; the study arms will be compared using chi-square tests and logistic regression to see if the attrition rate differs by arm and to compare baseline characteristics of participants who did and did not complete follow-up. Of those who complete follow-up, each variable will be examined for the presence of missing data, and if > 10% is observed for primary or secondary outcomes, then sensitivity analyses will be performed using complete case analysis or multiple imputation methods assuming data are missing at random (MAR). The MAR assumption indicates that the propensity for missingness does not depend on the unobserved outcome but rather is related to some other observed data.Special care different from the patient’s own reality will not be applied during the course of the trial; that is intended to resemble the real clinical applicability of the treatment as much as possible. In those patients who take opioid and non-opioid analgesics and/or neuromodulators as usual, medication will be documented in the baseline and follow-up controls. Likewise, if a patient undergoes any infiltration or surgical intervention in the same area affected by the trial intervention, this patient should be excluded from the clinical trial algorithm, and their data may not be used in the results from the date of surgery or infiltration {11d}.This study intends to adopt a rigorously designed and implemented randomized controlled method to evaluate the efficacy and safety of the administration of PRF therapy, combined with ACS, on the DRG to reduce neuropathic pain in patients with persistent LRP. The aim of this study is to explore a treatment with greater efficacy and fewer side effects for patients with persistent LLR, who have found pharmacologic therapy, corticoid injection therapy, or surgery ineffective. This treatment, if proven effective, may then be used as a complementary treatment to a more persistent pain.A number of clinical studies show that ACS (Orthokine®) therapy reduces pain and improves function, mobility, and health-related quality of life. Patients can be treated safely and effectively, and no other injection therapy  rivals its long-term efficacy in osteoarthritis or musculoskeletal pathologies –37. The To date, only the randomized clinical trial by Becker et al. has shown superiority of ACS over corticosteroids in lumbar radicular pain  . Godek eIn all cases, there were no undesirable or secondary effects due to ACS that made the studies reconsider in terms of safety. There is even a randomized pilot study also by Goni in which ACS injections were at cervical epidural level and in which pain improvement was obtained compared to methylprednisolone .The data, daily regular use, and yearlong experience suggest ACS (Orthokine®) serum is an effective and well-tolerated alternative to other injection therapies.As Kuffler explains , the triIf the hypothesis proposed in the study is proven, a great advance will be made in the treatment of LLR and even further neuropathic pain. If there is an improvement in pain in these patients and this has repercussions on an improvement in their quality of life and functionality, we will not only be contributing to the clinical improvement of pain itself but also contributing to the emotional and psychological part of life of these patients, transforming pain into a minimal symptom for it to cease to be a disease.Furthermore, as future therapies, it will give rise to a new gateway to future applications of the ACS as a molecular therapy on other types of neuropathic pain such as trigeminal neuropathy, peripheral neuropathy, and syndrome of the complex regional pain, among others.The protocol version number: 2, 1 September 2021.Date recruitment began: 1 February 2022.Approximate date when recruitment will be completed: 1 February 2024.Additional file 1. Annex I


Background: Diagnostic and treatment delays have caused significant impacts on the physical and emotional well-being of adolescents with endometriosis, though such research is limited. This study aimed to assess the effects of one-year dienogest therapy on the clinical picture, pain patterns, psycho-emotional status, and quality-of-life indicators in adolescents with endometriosis after surgical treatment. Methods: The study enrolled 32 girls aged 13–17 with peritoneal endometriosis to analyze one-year dynamics of the Visual Analog Scale (VAS), McGill Pain Questionnaire, Beck Depression Scale (BDI), Hospital Anxiety and Depression Scale (HADS), Spielberger State-Trait Anxiety Inventory (STAI) and SF-36 quality-of-life survey scores along with clinical and laboratory indicators before surgery and after one-year dienogest therapy. Results. The therapy provided a significant alleviation of endometriosis-associated clinical symptoms, including dysmenorrhea, pelvic pain, gastrointestinal/dysuria symptoms, decreased everyday activity (<0.001), a decrease in anxiety/depression scores , and quality-of-life improvement (<0.001). These effects were accompanied by beneficial dynamics in hormone and inflammatory markers  within reference ranges. A low body mass index and high C-reactive protein levels were associated with higher VAS scores; a high estradiol level was a factor for anxiety/depression aggravation (<0.05). Conclusions: Dienogest, after surgical treatment, significantly improved quality of life and reduced pain symptoms while showing good tolerability and compliance, and reasoning with timely hormonal therapy in adolescents with endometriosis. Clinical symptoms of endometriosis (EMS) develop starting from puberty, though in rare cases, the disease can manifest long before menarche . EpidemiChronic pain substantively contributes to affective disorders; in particular, chronic pelvic pain has been pathogenetically linked to depression ,9. PersiAdolescents diagnosed with a chronic and painful disease, in particular, experience increased emotional vulnerability and difficulties in coping with the illness, causing frustration, depression, and a lack of understanding of their condition along with physical, hormonal, and emotional changes related to the crucial time of puberty . Self-esA relationship between mental health and inflammatory status was evidenced in a number of studies ,19,20,21Systemic inflammation is a core link in EMS pathogenesis. Estradiol is known to directly stimulate prostaglandin E2 synthesis, thereby enhancing noxious stimuli in a COX2-dependent manner . Many stAmid the lack of unified opinions on whether inflammation should be considered a primary cause of EMS or a secondary factor in its transition to the chronic phase , there aThis study aimed to assess the effects of one-year dienogest therapy on the clinical picture, pain patterns, psycho-emotional status, and quality-of-life indicators in adolescents with peritoneal EMS.The study enrolled 32 patients with a confirmed diagnosis of peritoneal EMS, aged 13–17 at diagnosis, receiving inpatient/follow-up outpatient care at the Pediatric and Adolescent Gynecology Department, Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology. In addition, 43.8% (14/32) of girls had an association with peritoneal endometriosis and diffuse adenomyosis, according to imaging data (US and MRI). The clinical picture and pain patterns were assessed before the commencement and after one year of therapy. Dienogest was used as a first-line conservative pathogenetic option in accordance with the current guidelines (2 mg dienogest daily continuously for 1 year) for postoperative prevention of pain recurrence for at least a year . The menInclusion criteria: age 13–17; menstrual history; clinical symptoms of persistent moderate-severe dysmenorrhea or/and chronic pelvic pain resistant to NSAIDs; diagnosis of peritoneal EMS laparoscopically confirmed after the instrumental examination ; laboratory test data availability; written informed consent for the study. The indications for laparoscopy included unsuccessful empirical treatment  or persistent moderate/severe dysmenorrhea with negative imaging results. Data from the laparoscopic picture included surgical diagnosis and the stage of endometriosis according to the revised American Society for Reproductive Medicine (rASRM) criteria. In each case, we preferred an excision of the peritoneal foci; coagulation was performed in less accessible places.Exclusion criteria: aged over 18; somatic/endocrine/oncological comorbidities; infectious diseases; genital malformations interfering with menstrual outflow; pelvic tumors; mental conditions; laboratory/clinical data missing; informed consent missing.Study design: retrospective longitudinal observational cohort study. All patients underwent a full clinical/laboratory examination and passed the full survey before and after the one-year dienogest therapy.Clinical data collected for the study accounted for menstrual history, pelvic pain history , trends in pain intensity since menarche, specific factors aggravating the pains, and the family history of gynecological disorders all contribute.Laboratory tests included a general blood test: complete blood count (CBC), white blood cells (WBC), red blood cells, platelets, hemoglobin, hematocrit (Hct), and erythrocyte sedimentation rate (ESR). In the biochemical profile, the concentrations of total protein, uric acid, creatinine, direct and total bilirubin, glucose, Ca2+, Fe2+/3+, and highly sensitive C-reactive protein (CRP) in venous blood were determined for all participants. On the 3rd to 4th day of a spontaneous menstrual cycle, all girls included in the study were subjected to an extended analysis of the blood hormonal profile: the levels of the luteinizing hormone (LH), thyroid-stimulating hormone (TSH), thyroxine, follicle-stimulating hormone (FSH), dehydroepiandrosterone sulfate (DHEAS), androstenedione, prolactin (Prl), estradiol (E2), cortisol, testosterone (T), sex hormone-binding globulin (SHBG), and tumor markers Ca-125 and Ca-19-9 were determined. Hormonal assays were carried out by electro- and immunochemiluminiscent methods on Cobas e 411 , Immulite 2000, and Immulite 1000  automatic analyzers using reagents of the same companies. The concentrations of anti-Mullerian hormone (AMH) and 17-OH-progesterone (17-OHP) were measured by the enzyme-linked immunoassay on the DYNEX DSX System analyzer and using the Diagnostic Products Corporation (DPC) system on the Immulite device .(1)Pain scoring ;(2)Anxiety/depression surveys (Beck Depression Index (BDI); Spielberger State-Trait Anxiety Inventory (STAI); Hospital Anxiety and Depression Scale (HADS));(3)Quality-of-life scoring (36-Item Short Form Survey);(4)Interview, concerning negative emotional sensations/ psychosomatic complaints/ fatigue .The tests and interview included:The Visual Analog Scale pain scoring (VAS) uses a 10 cm horizontal line segment symbolizing pelvic pain intensity. The patients were asked to place a mark corresponding to their sensations. The distance between the lower end of the segment (‘no pain’) and the mark was measured in cm (points). Pains below 2 points were rated as ‘weak’, 2–4 points as ‘moderate’, 4–6 points as ‘strong’, 6–8 as ‘very strong’, and over 8 points as ‘unbearable’ .A Short-Form McGill Pain Questionnaire 2 (SF-MPQ-2) comprises 22 items exploring 4 domains: constant pain, periodic pain, neuropathic pain, and affective descriptors. The questionnaire includes the list of words to be used for the description of experienced pain qualities and associated symptoms. Each patient was asked to rate the intensity of specific pain sensations experienced over the past week on a scale from 0 to 10, where 0 stood for ‘no pain’, and 10 stood for ‘the worst pain imaginable’ .The Beck Depression Inventory (BDI) is one of the most common tools to assess the severity of depression in adults and adolescents, consisting of 21 items rated on a 4-point rating from 0 to 3. Interpretation is based on the total score and can range from 0 to 63. BDI scores above 9 points indicate depression: mild , moderate (16–19 points), medium severity (20–29 points), or severe (30–63 points) [The Spielberger State-Trait Anxiety Inventory (STAI) is one of the most widely used tests in clinical settings for the assessment of anxiety as a combination of two components: inherent  and reactive . It consists of 40 items ranging from Almost Never (0) to Almost Always. The scores are classified as low (≤30 points), moderate (31–44 points), and high (≥45 points); the combined output is used as a measure of the stress burden [The Hospital Anxiety and Depression Scale (HADS) consists of 14 items, each with 4 response options reflecting the degree of symptoms. The anxiety and depression subscales were scored separately. The interpretation involves the total scores for each subscale rated as follows: ≤7, norm (the lack of symptoms); 8–10, subclinical anxiety/depression; ≥11, clinical anxiety/depression [Quality of life (QoL) was assessed using the 36-Item Short Form Survey (SF-36) comprising 36 items grouped into 8 domains: physical functioning, role-related activity, bodily pain, general health, vitality, social functioning, emotional state, and mental health. Each domain earned 0–100 points, and all scores jointly contributed to mental and physical well-being indices .The personal interview included, in addition, questions regarding the characteristics of stressful tension and psychosomatic manifestations. The interview consisted of a list of questions accounting for autonomic nervous system manifestations of subjective stress burden, including cardiovascular symptoms , respiratory symptoms , gastrointestinal symptoms , fainting, paroxysmal headaches. The test also accounts for neuroticism (degree of anxiety), overall life (dis)satisfaction and difficulties concentrating, sleep characteristics , as well as in family, school and personal relationships. Patients were asked to answer each question in three ways  to describe their sensations. Additionally, patients answered the questions about emotional reactivity (nervous flashes), attitudes towards social environments , and the frequency of depressive and anxiety symptoms , experienced during the last month.p < 0.05. Correlations were estimated using Pearson’s correlation coefficient  or Spearman’s rank correlation method (nonparametric). The influences of categorical factors and quantitative variables were estimated by factorial ANOVA and multiple logistic regression methods, respectively.Statistical analysis was carried out using IBM SPSS Statistics 28.0.1 and Statistica V10 Statsoft software. The distribution normalities were challenged with a Shapiro–Wilk test. The normally distributed variables were described by means (M) and standard deviations (SD). The therapy-related dynamics were estimated using paired Student’s t-test for measured variables and χ2 McNemar’s test for dependent proportions; the trends were considered significant at Ethical approval: the study was approved by Biomedical Ethics Committee at the Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology (Protocol No. 9 of 2020-10-22). All participants  provided written informed consent for inclusion in the study, the use of medical data/images, and publication of the findings.In the studied sample, the majority of adolescents were characterized with the I stage of endometriosis according to the revised American Society for Reproductive Medicine (rASRM) score  score). The rest of the patients had the II stage ) and the III stages of the disease  score). The III rASRM stage of the disease in two cases was observed on the background of adenomyomas (O2/0), and, in three cases, adhesions on the tubo-ovarian unit (T1/0) were detected.2; specifically, <18 kg/m2 in 37% (12/32), 18–25 kg/m2 in 47% (15/32), and >25 kg/m2 in 16% (5/32) of the cohort. Most of the patients had a regular cycle established immediately  or 1-year post-menarche , and 44.8% of the cohort (14 patients (pts)) had an irregular cycle. Menstrual abnormalities included a shorter menstrual cycle , prolonged menses , and ‘heavy’ menstrual flow .All patients of the cohort had menarche for the first bleed at the age of 11–15 years. The body mass index (BMI) at admission was 20.6 ± 3.4 kg/mA third part of the patients  reported non-menstrual vaginal bleeding, including mid-cycle spotting (7 pts) and appearance of discharge 3 days before (4 pts) or 3–5 days before and after each period (2 pts). Among patients with non-menstrual bleeding, 56% (5 pts) had a combined diagnosis of ‘peritoneal EMS/adenomyosis’, and 44% (4 pts) were diagnosed with ‘peritoneal EMS’ only see .The majority of patients experienced menstrual pain starting from menarche  or 1.5–2 years post-menarche . In minor proportions of cases, the pains started 0.5 years post-menarche (2 pts) or were supposedly incited after genital inflammation (1 pt) or after abdominal surgery (1 pt) see .Most patients  considered their pain as of constant intensity (in retrospect), whereas in 46.9% (15/32), the intensity increased over time since menarche see a.When asked to attribute pelvic pain to the course of the menstrual cycle, 34.3% (11/32) of the patients reported mid-cycle pain, and lower proportions reported pain experienced daily , 1–3 days before menses and that which lasted for several days  or 3–5 days before and after each period . In single cases, the pain was experienced a week before or >5 days before and after each period. The structure of pelvic pains as related to the menstrual cycle is shown in The majority of patients described pain in the lower abdomen ‘above the pubic region’ , lumbar , and/or diffuse pains without clear localization . Other specific sites of painful sensations included the groin area on the left , groin area on the right , perineum (2 pts), or sacrum .The painful sensations were subjectively specified as ‘dull, nagging’ by 43.8% (14/32) of the patients, whereas 25.0% (8/32) referred to it as ‘spasmodic’. In addition, 21.9% (7/32) had ‘stabbing’ pains, 9.4% (3/32) reported ‘pressing’ pains, and 1 pt defined her sensations as ‘burning’ (the patients could provide more than one definition).Other clinical signs of EMS included menstruation-related gastrointestinal symptoms  in 40.6% (13/32) and dysuria in 18.8% (6/32) of the patients. When asked about specific circumstances of pelvic pain worsening , the patients ticked the ‘beginning of menses’ , ‘physical motion’ , ‘urination’ , and ‘during/after defecation’ . Additionally, 1 pt reported pain worsening after hypothermia or swimming in ponds or pools, 1 pt related it to overheating , and 2 pts  admitted pain worsening during/after sexual intercourse see .Of note, 62.5% (20/32) of the patients reported having female relatives  with a history of EMS or abnormal uterine bleedings, and 50.0% (16/32) reported a family history of chronic pelvic/menstrual pain.p < 0.001)  from severe (8.3 ± 1.6 points) to mild, approaching physiological levels (1.7 ± 2.1 points) (< 0.001) .The persistence of the pain also showed distinct progestin therapy-related dynamics. Before therapy, 97% (31/32) of the patients experienced pain every menstrual cycle, and only 1 pt reported occasional menstrual pain (≤4 episodes a year). The therapy afforded the cessation of menstrual pain in most of the cases, with the rest of the cohort reporting occasional pain (≤4 episodes a year); in several cases, the pain remained in at least every other cycle (2 pts) or experienced persistent cyclic pain (2 pts) see .The initially high proportion of patients with non-menstrual vaginal bleeding  after one-year dienogest therapy was reduced to 12.5% (4/32). Of note, 41% (13/32) of the patients reported a lack of menstrual bleeding during the therapy, which was considered indicative of efficacious therapy.In addition, the proportion of patients with non-menstrual pelvic pain  after one-year dienogest therapy was reduced to 10% (3 pts). The multiple-dose use of painkillers for dysmenorrhea was also considerably reduced .In addition, therapy significantly reduced the incidence of other EMS-associated complaints, including decreased everyday activity/performance and gastrointestinal or dysuria symptoms .The observed alleviation of dysmenorrhea during the treatment was supported by corresponding dynamics not only of VAS but also of McGill Pain Questionnaire scores. One year after the commencement, the test revealed significant decreases in constant/periodic/neuropathic pain and affective pain descriptor scores. These results not only confirm the therapy-related pain alleviation but also indicate a significant contribution of the subjective perception of noxious stimuli (as measured by affective pain descriptors) to the overall severity of EMS-associated pain syndrome .Apart from the reduced severity of EMS-associated pains, the cohort revealed the significant mitigation of affective states/sensations during the therapy . Beck’s QoL dynamics for the cohort indicated a significant improvement and approached a state of complete health (100 points) as measured by physical component, psychological component, and average QoL scores on the background of the therapy .As revealed by the interview, the therapy significantly reduced the incidence of heart palpitations and heavy breathing symptoms, possibly regarded as subclinical autonomic neuropathy/dysfunction, at the cohort level. The therapy-related dynamics of fainting episodes and recurrent headaches  were negligible. A beneficial trend for recurrent paroxysmal headaches may reflect the overall pain-relieving efficacy of progestins for the studied cohort. Incidentally, the lack of significant dynamics for headaches, which may arise as a side effect of progestin intake, further justifies the continuous medication protocol. In the study sample, one patient noted an increase in body weight (3.1%), four patients noted a decrease (12.5%) compared to the initial BMI, and the rest of the girls did not notice a change in weight during dienogest therapy. The lack of significant dynamics for BMI during treatment, which is especially important for adolescents, also indicates good tolerability and contributes to high satisfaction with the treatment reported by participants.In addition, the decrease in cognitive/affective signs, including mild memory difficulties, explosiveness (uncontrollable nervous flashes), nervousness/tension/anxiety, and fear/panic attacks, was also revealed by the interview see . In addiPeripheral blood tests revealed a decrease in testosterone, estradiol, prolactin, cortisol, and CA-125 levels, and neutrophil-lymphocyte count ratio during the one-year dienogest therapy  amid an increase in LH and FSH levels .p = 0.004), HADS depression , and Spielberger’s ‘reactive’ anxiety  scores, as well as the McGill affective pain descriptor and constant pain scores . In addition, lower BMI and higher CRP were identified as significant independent factors of a high VAS score , whereas FSH levels significantly influenced physical well-being as assessed by SF-36 .A multifactor regression analysis involving objective and subjective parameters was carried out to identify the predictors of affective signs among clinical and laboratory indicators and ultimately to assess the efficiency of dienogeat therapy in young patients with EMS. According to the results, elevated estradiol levels represented a significant independent predictor of high HADS anxiety , as well as the averaged QoL score , as assessed by SF-36. Apart from BDI, the QoL psychological component was negatively influenced by pain intensity , HADS anxiety , and HADS depression  scores. The QoL physical component was negatively influenced by pain syndrome indicators, including VAS  and McGill’s constant , neuropathic  and affective pain descriptor  scores.Another aspect was the interaction of subjective factors with affective signs persistence. Significant predictors of high BDI scores included low scores for physical and psychological QoL components , STAI-T  and HADS anxiety  subscales, respectively.It is important to highlight the prognostically meaningful connection between levels of certain hormones before the therapy and the degree of anxiety-depression signs even one-year post-commencement, notably the influence of initial estradiol levels on final scores for STAI-S  with pain sensations varying in character , indicate the presence of a neuropathic component. The variations can be explained by the complex topography of immune dysregulation and shifted macrophage equilibria, as well as the estrogen-induced innervation of the lesions. The estrogen-dependent inflammation in EMS foci triggered multiple mechanisms of sensory and sympathetic neurogenesis amid the gradual aggravation of the local pro-inflammatory status. The persistent cytokine-induced stimulation of nociceptors facilitates neuroinflammation through the release of inflammatory neurotransmitters. The results of conducted multivariate analysis linked CRP levels to the VAS score and estradiol levels to the McGill pain index. Our data fit into the conception that estrogen-induced neuro-immune interaction plays a key role in peripheral sensitization while enhancing EMS-associated neuropathic pains ,25,26.p = 0.009). This finding is consistent with the reported positive influence of severe dietary restrictions combined with high physical activity  on EMS progression by Reis F.M., Coutinho L.M. et al., 2020 [Correlations between BMI and an affective component in EMS are of special clinical interest. Interaction between these parameters is revealed by factorial analysis , reduced intermenstrual pain incidence (p < 0.001), and reduced NSAID intake (p < 0.001). The achieved therapeutic effect apparently involved the COX-dependent suppression of prostaglandin synthesis by NSAIDs, prolonged and complemented by the anti-inflammatory action of, which are known to inhibit the production of pro-inflammatory TNF-α, IFN-γ, and IL-12 and activate the synthesis of anti-inflammatory IL-10 in EMS foci. In addition, progestins are known to reduce the pro-inflammatory impact of antigen-presenting cells, notably dendritic cells, while supporting the regeneration and functional maturation of epithelial lining in the uterus [EMS can be treated either hormonally or surgically, with laparoscopy remaining the gold standard for its diagnostics in all susceptible age groups. Progestins-based regimens are considered a first-line pathogenetic option in EMS, with minimum risks and maximum clinical benefits . A studye uterus .p = 0.000 for each). Before the therapy, patients experienced moderate reactive/high inherent anxiety (Spielberger’s) and sub-depression (BDI). The reduction in scores to normative values indicated a substantial improvement in the psycho-emotional status of the patients. Apparently, this recorded decrease in pain intensity eventually alleviated the distress associated with the expectation and sensation of cyclic and non-cyclic pains, annoying (sometimes to the point of exhaustion) and interfering with everyday activities [p = 0.001) and heavy breathing , as well as neurotic signs  and cognitive impairment . Our data support a close relationship between the degree of EMS-associated pains and anxiety/depression signs originating in adolescence [The therapy also alleviated affective symptoms as measured by BDI, including Spielberger’s reactive/inherent anxiety subscale scores and HADS anxiety and depression scores . These therapy-related positive dynamics can be explained by the alleviation of both physical symptoms and mental complications  of the disease. The alleviation of physical symptoms is indicated by the significantly reduced proportion of patients reporting hampered everyday activity, weakness, and declined capabilities during menses, gastrointestinal symptoms, and dysuria after the therapy. Our data are consistent with the results of Mińko A. et al., relating to a pronounced decrease in the quality of life and higher rates of depression and anxiety scores in patients with endometriosis [Furthermore, the study revealed a significant improvement in life quality indicators during therapy, including ‘physical’, ‘psychological’, and ‘overall life quality’ domains , indicate that this therapy does not induce hypothalamic-pituitary-ovarian/adrenal axis destabilization. In addition, we observed a significant decrease in the neutrophil-to-lymphocyte count ratio and CA-125 levels, accompanied by a similar trend for CRP; these dynamics may also indicate the alleviation of inflammatory processes by continued therapy.p = 0.004, p = 0.033 and p = 0.046, respectively). Still, published evidence on the influence of estrogens on psycho-emotional status is controversial. It is conventionally maintained that estrogens boost noradrenalin and β-endorphin synthesis while inhibiting monoamine oxidases and modulating dopamine receptor activities in brain tissue, thereby promoting anxiolytic and anti-depressant effects [The search for predictors of affective disorders among clinical and laboratory parameters identified high estradiol levels as an independent significant positive factor of HADS anxiety, HADS depression, and Spielberger’s reactive anxiety scores ( effects . The mec effects . Therefo effects .p < 0.05 for each) domains as significant predictors of depression (as assessed by BDI). Apart from the BDI score, life quality indicators negatively correlated with the VAS score for pain intensity and HADS scores for anxiety and depression (p < 0.05 for each). In addition, subjective indicators of psycho-emotional status and life quality were interrelated: for instance, psychological well-being significantly reflected HADS scores and BDI, while physical well-being reflected McGill scores for constant/neuropathic pains and affective pain descriptors, and both psychological and physical domain scores significantly reflected the VAS score. These results are consistent with the supposedly central role of pain syndromes in an EMS-associated sense of physical and psychological deprivation [The comparative assessment of psycho-emotional factors in the structure of the affective component identified low SF-36 scores in physical, psychological, and average QoL (rivation .p = 0.05). Despite the lack of significant therapy-related dynamics for the studied cohort, CRP levels could be used to estimate the grade of inflammatory process on an individual basis.The search for biochemical predictors of EMS symptom severity identified CRP levels as an independent significant correlate of the VAS score (p < 0.005), which can reflect the increased production of estradiol by active EMS foci and stress responses to persistent noxious stimuli leading to central and peripheral sensitization. No specific relationships between hormone levels and psycho-emotional characteristics in adolescents with EMS have been described so far [Estradiol levels significantly influenced McGill scores for constant pain and affective pain descriptors  enrolling matched conditionally healthy individuals and/or patients receiving alternative treatment or non-receiving progestins after surgery treatment).Thus, adolescent patients with genital EMS are likely to develop characteristic symptoms of mood disorders; importantly, this tendency was revealed by different questionnaires. The collected data indicate high-stress susceptibility and the aggravation of affective symptoms/neuroticism in adolescents with a distinctive clinical picture of EMS, especially against the background of non-effective symptomatic treatment.It should be noted that EMS-associated chronic pain management in adolescents is often more complicated than in adults, as the therapist has to explicitly communicate with both the patient and her parents. In addition, every clinical decision must account for the young age of the patient to ensure her long-term emotional/physical/sexual well-being and fertility. On one hand, persistent pelvic pains can promote mood disorders  or aggravate them. On the other hand, adolescents with signs of depression/anxiety may have an exaggerated perception of painful experiences and are more likely to develop inadequate coping strategies, e.g., social isolation . The conIt is important to emphasize that the elimination of clinical signs in EMS does not ensure the compensation of a serotonin system deficit. In this regard, young patients with EMS-associated chronic pelvic pain may substantively benefit from pathogenetically justified psychotropic medication regimens .Considering the multiple systemic effects of EMS, the comprehensive pain-focused treatment schemes accounting properly for psychological consequences are advantageous. To provide maximum relief, the management should be accomplished through coordinated efforts of gynecologists, psychiatrists, psychologists, and physiotherapists. A solid body of research evidence identifies juvenile EMS as a key medical and social issue requiring advanced diagnostics and management with a mandatory account for psycho-emotional and life-quality indicators.p < 0.001 for each). The therapy afforded significant relief of affective symptoms  and quality-of-life improvement ;After one-year dienogest treatment, the patients reported significant alleviation of the severity of dysmenorrhea and EMS-associated symptoms, including pain-related decreases in daily activities and performance; gastrointestinal/dysuric symptoms  were encountered, although 13% of the adolescents reported episodes of spotting. The therapy promoted a decrease in blood levels of hormones and inflammation markers  within reference ranges.Estradiol levels provide a significant predictor for affective disorders in adolescents with endometriosis before treatment  and after the therapy (STAI and HADS anxiety scores), whereas BMI and CRP levels are, respectively, negative and positive factors of pain syndrome severity.


As primary outcomes differ among clinical lumbar disc herniation (LDH) studies, this study aimed to explore outcomes reflecting real-world patient experiences through an exploratory questionnaire survey. Those diagnosed with LDH having radiating leg pain in South Korea in November of 2022 (N = 500) were administered a questionnaire including basic characteristics, disease onset, symptoms and severity, priority symptoms for improvement, and important treatment factors. Outcome measures included the identification of priority symptoms and disabilities. Most common symptoms were numbness in the leg  and back pain ; most common disabilities were discomfort in sitting  and lifting . The highest priority symptom was back pain . A satisfactory degree of symptom improvement was a decrease of at least 3 points on the numeric rating scale. The majority of respondents preferred improvement in disability over pain , a stable effect over a rapid effect , and safety over treatment efficacy . Safety  and cost  were the most important treatment factors. Improvements in back pain, leg pain, sitting, and sleeping were prioritized, and safety, stable treatment effect, and functional recovery were desired. Clinical trials for LDH should be designed to reflect this real-world patient need. Further study to examine the patients’ symptoms and needs in details is needed. Low back pain (LBP) and radiating leg pain are highly prevalent worldwide, with the lifetime prevalence of LBP being as high as 66% . MoreoveThe causes of back pain are myriad, the most common of which is lumbar disc herniation (LDH) . In LDH,Accordingly, many clinical trials on LDH have been conducted or are underway. An important aspect of designing clinical trials is the selection of outcomes in the target population to whom the results will be applied. Particularly, in clinical studies evaluating the effectiveness of specific treatments, the priority outcomes that reflect real-world symptoms and conditions are instrumental.The numeric rating scale (NRS) scores for radiating leg pain, Oswestry disability index (ODI) score, and Roland–Morris disability questionnaire (RMDQ) score are commonly used as primary outcomes. The NRS is a numeric pain scale for the objective representation of subjective pain felt by individual patients (0 representing no pain and 10 representing the worst pain and discomfort imaginable) . The ODIDespite these differences, no study has yet discussed the rationale for selecting these primary outcomes or their priority over other outcomes. In addition, the effects of treatment cannot be fully elucidated with a limited number of outcomes. Therefore, this questionnaire survey study aimed to explore the most appropriate outcomes to reflect the real needs and concerns of patients with LDH and provide guidance for outcomes in clinical trials.This cross-sectional nationwide web-based survey study was conducted using Opensurvey, a Korean mobile application survey company. Opensurvey selected respondents who met the inclusion criteria through a screening survey, stratified the respondents by age and sex, and distributed survey links. A total of 500 respondents were selected from 100 participants per age group, and the survey link was closed after the selection was completed. Survey data were collected between 15 and 16 November 2022.Before commencing the survey, all respondents were asked to indicate their willingness to participate by checking an online consent form that included a brief introduction to the study, inclusion/exclusion criteria, and a confidentiality clause. Only the patients who agreed to participate were administered the survey. The survey was conducted anonymously, and personally identifiable information was encrypted and provided only to the investigators.The inclusion criteria were as follows: diagnosed with LDH by clinicians through clinical symptoms, physical examination, and radiological assessment; age of 19–69 years; presence of LDH-related symptoms such as pain, numbness, weakness, or tingling in the legs; and agreement to sign the informed consent form. Although magnetic resonance imaging (MRI) is considered the most appropriate test to confirm the presence of LDH , LDH canIt was judged that 100 people per age group was the minimum number to produce meaningful statistics; thus, a total of 500 respondents  were recruited using age-stratified sampling with nationwide panels. It was also determined by referring previous study that of 500 was “very good” for a survey study  and thatThis study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Jaseng Hospital of Korean Medicine . Written patient consent forms were waived owing to the study design as a mobile application survey, and all participants expressed their consent by checking the consent form provided online. If a patient declined participation or withdrew consent, the collection of personal information was immediately discontinued, and the information discarded.The questionnaire was developed based on previous studies ,11,23 anBasic characteristics included sex, age, area of residence, and occupation. Age was categorized into the 20s (including age 19 years), 30s, 40s, 50s, and ≥60s groups. The area of residence was classified into Seoul, the capital area, metropolitan cities, and other areas. Occupations were classified according to the Korean Standard Classification of Occupations guidelines as follows: managers; professionals; clerks; service workers; sales workers; skilled agricultural, forestry, and fishery workers; craft and related trade workers; plant and machine operators and assemblers; elementary occupations; armed forces occupations; and people without formal occupation (including housewives and students).The first onset of symptoms and recent onset including recurrence and exacerbation were investigated. The onset was selected from the following ranges: ≤4 weeks, 4–12 weeks, 12 weeks to 12 months, and ≥12 months. In addition, the time of LDH diagnosis and whether the respondent underwent MRI scans at the time of diagnosis were also determined. The specific time point and event that triggered the symptoms were investigated by asking the respondents to provide a written description.LDH symptoms were classified into symptoms and disabilities. Symptoms were classified as back pain (excluding pelvic and hip pain), pelvic pain (including hip pain), radiating leg pain, numbness in the leg, weakness in the leg, and tingling in the leg (feeling as if the skin of the affected area was someone else’s skin or having a dull sensation) for a more objective assessment. In addition, the severity of each symptom was evaluated using the NRS ,25, a nuMeanwhile, the types of disability included were classified as discomfort in personal care , lifting, walking, sitting, standing, sleeping, and traveling (including driving); impacting social life ; anxiety/depression; productivity loss; and gastrointestinal problems (from medications for LDH symptoms). The severity of each disability was also assessed using categorical options based on the ODI. The disability severity questionnaire is presented in The respondents prioritized symptoms for improvement by selecting one symptom each for the following questions “What is the symptom you would like to improve the most?” and “What is the symptom you would like to improve the second most?” For each selected symptom, the respondents then answered the following question using numbers from 0 to 10: “What NRS score would you consider for a satisfactory level of improvement for the selected symptom?” In the instance that respondents listed only one symptom, they did not respond to the question about the second symptom. Similarly, the first and second disabilities that the respondent aspired to improve the most were selected. The satisfactory level of improvement for the selected type of disability was classified based on answers of improvement of 100% , 80% or more, 50% or more, 30% or more, and 20% or more.Participant opinion on important factors of treatment was assessed by asking the participants to select between reduced pain and improvement in functional disability, between rapid effect and stable/lasting effect even if the improvement was slow, and between treatment effect and safety. In addition, patients were asked to choose three items in order of importance from appropriate cost, non-painful and comfortable treatment, rapid effect, overall condition, safety, time taken for treatment, and duration of improvement.A frequency analysis was performed for each respondent characteristic for the survey responses, and a two-tailed test was used to perform the statistical analysis, with the significance level set at 5%. As for basic characteristics, categorical variables are expressed as the frequency and percentage , while continuous variables are expressed as the mean and standard deviation.The presence or absence of each symptom caused by LDH is reported as the frequency and percentage , and the differences in the rate of each symptom according to sex, age, symptom duration, and severity of symptoms were tested using the chi-square test.Regarding disability, the status of presence or absence is reported as frequency and percentage , and the difference in the incidence of each disability according to sex and age was analyzed using a chi-square test or Monte Carlo simulation method ,27.The types of symptoms and disability requiring priority in improvement are reported as the frequency and percentage . The frequency and percentage were calculated for responses including only the first priority and both the first/second priorities. In addition, the percentage of patients with each symptom and disability was calculated. Differences by respondent characteristics were tested using the chi-square test. For symptoms, differences were tested according to sex, age, symptom duration, and severity of symptoms; for disability, differences were tested according to sex and age.The satisfactory improvement score was calculated as the difference in the current symptom score from the satisfactory improvement score. Scores are expressed as the mean ± standard deviation. If the difference between the initial response value and the satisfactory improvement score was negative, the response was judged to be unreliable and was excluded from the calculation. Differences in satisfactory improvement scores by respondent characteristics were tested using analysis of variance. For disability, the percentage of respondents who responded that they would be satisfied with an improvement of 80% or more was determined, and differences by sex and age were tested using the chi-square and Fisher’s exact tests.The distribution of important factors of treatment according to respondent characteristics is expressed as the frequency and percentage , and differences by sex, age, symptom duration, and severity of symptoms were tested using the chi-square test. A multivariate logistic regression model was used to analyze factors that influenced what patients considered more important in treatment. Sex, age, onset, and severity were used as covariates. All estimates are expressed as adjusted odds ratio (OR) and 95% confidential interval (CI). The area under the curve (AUC) was presented to evaluate the goodness of fit for the logistic regression model.Unmet medical needs and intention for treatment according to respondent characteristics are expressed as the frequency and percentage , and differences by sex and age were analyzed using the chi-square and Fisher’s exact tests.For sensitivity analysis, the analysis only for patients diagnosed with LDH on MRI was performed. All statistical analyses were performed using R-4.2.1 for Windows (The R Foundation).In total, 9680 respondents were screened, with 9000 excluded for not meeting the inclusion criteria. Of the 680 respondents who met the inclusion criteria, 35 rejected the main survey and 145 failed to return it; thus, a total of 500 people responded to the main survey .A total of 9680 patients were screened and 680 were invited to the main survey. Ultimately, 500 patients who completed the responses completely were analyzed.The basic characteristics of the respondents are presented in p = 0.069), pelvic pain , and radiating leg pain  were higher in women. Meanwhile, the rates of weakness in the leg  and tingling in the leg  were higher in men. When only patients diagnosed with MRI were analyzed, the rates of each symptom and the distribution according to characteristics were similar (LDH symptoms are shown in  similar .p = 0.006), sitting , standing , and sleeping  were higher in women. In addition, the rate of productivity loss  was significantly higher in men. When analyzed by age group, the rate of disability was higher in the older age group. Particularly, the older age group showed significantly higher rates of difficulty in lifting (p = 0.034), walking (p = 0.003), and traveling (p = 0.022); hampered social life (p = 0.013); and psychological problems (p < 0.001), productivity loss (p = 0.012), and gastrointestinal problems (p = 0.001). This tendency was similar for patients diagnosed via MRI (Types of LDH-related disability are displayed in  via MRI .Symptom severity and disability are shown in The priority symptoms for improvement are shown in p = 0.005), while the priority for improvement in numbness in the leg was higher in men than in women .For patients diagnosed via MRI, the most prioritized symptom was also back pain , followed by numbness in the leg and pelvic pain. Sex differences were also similar .The respondent-defined average decrease in the NRS score for satisfactory symptom improvement is presented in For patients diagnosed via MRI, the satisfactory average change in the NRS score was also 3 or higher. Additionally, female patients with longer onsets and patients with more severe symptoms tended to desire greater levels of improvement .The priority disabilities for improvement are shown in p = 0.001) and productivity loss . Meanwhile, more female respondents desired improvements in discomfort in walking  and sitting  compared with male respondents. With respect to differences by age, the responses differed for each item rather than showing a consistent trend. Most respondents in their 30s prioritized improvement in lifting, those in their 60s prioritized improvement in walking, those in their 20s prioritized improvement in sitting, and those in their 40s prioritized improvement in traveling. There was a similar tendency shown among those who only underwent MRI at diagnosis . Regarding preference between rapid and stable effects without recurrence, the majority  of respondents chose the latter; regarding preference by symptom onset time, more stable effects were desired over rapid effects. Between treatment effect and safety, the majority  of the respondents preferred safety. Women placed a higher importance on safety than did men, and patients with chronic symptoms considered safety more important than did those with acute symptoms.The responses for important factors in treatment are shown in Patients diagnosed via MRI also preferred disability improvement, stable effects, and safety rather than pain reduction, rapid effects, and efficacy, respectively. Males preferred disability improvement more than female patients, and female patients and those with longer onsets tended to prefer safety .p = 0.021), indicating that females valued pain reduction over functional improvement compared to men (p = 0.005), indicating that patients with a longer symptom onset desired a stable effect. Regarding the importance of safety over treatment effect, the OR of female to male was 1.45 , and the OR of patients with an onset of 12 months or more to patients with an onset of 4 weeks or less was 2.37 . Overall, female patients prioritized safer treatments compared to male patients, and those with long-term symptoms did so compared to patients with short-term symptoms. The AUCs of the multivariate logistic model for functional improvement, stable effects, and safety were 0.61, 0.62, and 0.61, respectively.In factor analysis, the OR of female patients, using that of male patients as a reference, for the preference for functional improvement rather than pain reduction was 0.65  and cost . When the top three factors were considered, cost  and safety  were the most important factors B.Responses regarding unmet medical needs and intention to treat are shown in p = 0.001) and those who were in their 40s and older (p = 0.008). For the frequency and duration of medical care, the majority of the respondents selected 2–3 times  or once per week  and less than 1 h per treatment session .When asked whether they would wish to receive continued care even after improvement in symptoms, a significant proportion of the patients  expressed a desire for continued management. The preference for continued management was significantly higher in males  on the various outcomes of patients with LDH, MCID is typically expressed as a specific number and is not affected by the baseline value ,40,41,42Among types of priority disabilities for improvement, many respondents selected improvements in sitting, lifting, sleeping, and walking as priorities. However, productivity loss was the second most common response in those who experienced it. Given that productivity loss is directly related to livelihood, it can be assumed that it is a critical problem for patients with related problems. In fact, normal economic activity is an important goal of treatment and is also an important socioeconomic factor. However, studies that evaluated the effectiveness of treatment generally did not include outcomes related to economic activity. In most cases, economic activity is only included as part of a cost calculation for economic evaluation. Thus, it is suggested that related outcomes, such as return to work and productivity loss, should be considered in clinical trials for patients with LDH.Differences by sex were also identified in the types of priority disabilities for improvement. Male patients desired improvements in factors related to external activities such as traveling and productivity loss, while female patients desired more improvements in factors related to everyday activities such as walking and sitting. Instead of a consistent trend in differences by sex, there was no particular trend by age. Respondents in their 30s selected lifting disability as the first priority for improvement, those in their 60s selected walking, those in their 20s selected sitting, and those in their 40s selected traveling. More patients selected improvement in functional disability over that in pain reduction. However, the difference between the two was not large, and this tendency was greater in males. Pain and function are closely related factors, as they can act as both cause and effect and making dichotomous choices may have been difficult. This can be observed from the fact that the difference in preference for pain reduction and functional improvement was not large. Furthermore, pain and disability are different concepts, and the direction of changes in these outcomes is not always in agreement. In a study that analyzed the relationship among pain, disability, and quality of life in patients with LBP, improvement in pain did not lead to improvement in function or quality of life. Thus, it was concluded that outcome measures for pain and functional disability should be evaluated separately . TherefoIn addition, more patients selected a stable treatment effect over a rapid one and safety over treatment effects. Furthermore, patients with a longer duration of symptoms preferred treatment with stable effects over rapid effects and safety over treatment effects. Particularly, for the choice between rapid and stable treatment effects, approximately 80% of the patients selected stable effects, showing a clear pattern of preference. Nevertheless, outcome measures in clinical studies typically do not include the stability of treatment effects or recurrence. Most studies have focused on rapid effects such as survival analysis and degree of improvement within a set period. The findings of this study indicate that such outcomes may not reflect the real needs of the patients. Therefore, an outcome that could evaluate the stability of the treatment effect may be necessary, especially for clinical studies involving many patients with chronic conditions. Possible measures include the area under the curve within the follow-up period or the incidence of deterioration above a certain level after improvement. In this regard, strategies and methods for an effective evaluation of the stability of treatment effects should be cautiously considered.Notably, although the difference was not large, many patients responded that safe treatment had high importance. In particular, women and patients with longer duration of symptoms showed a tendency to prefer safe treatment. Interestingly, patients do not necessarily prefer treatment with rapid effects just because their symptoms are severe. Although it may be perceived that patients with severe symptoms would prefer a treatment with rapid effects, the current study showed that in the real world, these patients also desired safe treatment more. However, in clinical trials of specific intervention for patients with LDH, safety is rarely treated as an important outcome. Therefore, particularly in the case of chronic patients, it is necessary to investigate adverse events more thoroughly.In addition, approximately half of the respondents reported that they had unmet medical needs, and cost and time constraints were the major reasons for their unmet medical needs. In addition, more than 60% of patients responded that they preferred continued treatment despite symptom improvement. For the intention to receive treatment, most respondents preferred treatments once to three times weekly with a duration of less than 1 h per session. Ensuring treatment compliance is integral during clinical trials, and although the duration and frequency of treatment should be determined according to clinical judgment, there should be efforts to improve patient compliance by considering the patient’s intention for treatment as discussed above.Overall, the results of this study should be interpreted with caution because of several limitations. First, as this survey was conducted in Korea, it is questionable whether the results can be applied to general patients with LDH. In particular, there is a possibility that the results related to factors considered important in treatment or unmet medical needs reflect distinct characteristics of Korea.Secondly, as this study is an online survey, all data were self-reported. The same was true for the process of selecting respondents. That is, the diagnosis of LDH depended on the patient’s response. This may have affected the validity of the survey results. However, to increase the validity of the survey, responses with logical and formal errors between questions were deleted. Furthermore, this limitation can be observed in all survey studies, and a sample size of 500 is judged to guarantee the validity of the overall results despite the possibility of some unreliable responses. In this study, 2/3 of the patients responded that they had undergone an MRI at the time of diagnosis. The tendency of the overall results did not change, even in the sensitivity analysis on only patients who had had an MRI. These results further increase the validity of the actual LDH diagnosis of the respondents. The fact that 7% (680 out of 9680), the rate of satisfying the inclusion criteria in the screening questionnaire, was comparable to the Korean adult disc prevalence, may also be another rationale for validity.Thirdly, although MRI is the most appropriate method to confirm LDH, we did not include whether or not respondents were diagnosed via MRI as part of the inclusion criteria. Instead, we attempted to specify the inclusion criteria as much as possible through including only patients with radiculopathy and those diagnosed with LDH by clinicians. This decision was made based on the North American Spine Society’s evidence-based guideline suggesting that manual muscle testing, sensory testing, and supine SLR tests are the gold standards for clinical diagnosis of LDH . In contIn addition, the possibility of a selection bias toward people who proficiently use mobile phones and apps could not be ruled out. Moreover, there may be concerns regarding whether 500 respondents can represent all patients with LDH and whether this is a sufficient number. Determining a sample size is difficult. Of course, larger sample sizes are better, but they entail remarkable effort and time. We determined the appropriate sample size for this study to be 500 based on the literature  along wiAdditionally, COVID-19, which has been prevalent since 2019, has had a significant impact on individuals and may have influenced respondents’ thoughts in some way. This point was not considered in this study, but it would be a better study if the impact of COVID-19 could also be explored in future research.There were also limitations to the questions and questionnaire items themselves. A more in-depth analysis would have been possible if the survey had included more diverse items, such as body mass index, underlying disease, and genetic factors. In addition, although there may be points to consider in the clinical trial depending on the specific treatments, specific treatment that the patients received were not asked for in this study. However, this exploratory questionnaire was an analysis of outcomes that could be universally applied to any clinical trial for LDH patients. Nevertheless, there are cases where a specific outcome, such as reoperation, is the main outcome; depending on the type of intervention, the main outcomes are often related to pain and function regardless of the type of intervention in most clinical trials. Further, considering that an excess of complex questions may decrease the response rate and validity, and considering that this was an exploratory, descriptive study, we constructed the questionnaire with the minimal possible number of necessary items. In addition, MRI results were not asked for, as it was believed that most patients would not be aware of their MRI findings. If we had known the degree or type of disc herniation, we would have been able to conduct a more interesting analysis. However, the severity was classified depending on the patient’s clinical symptoms and subjective report. Furthermore, we attempted to include mental illness and intellectual disabilities as exclusion criteria, but these were ultimately not included because they were considered inappropriate in terms of application, and the validity of the response could not be guaranteed. Lastly, in survey studies, it is very important to present psychometric evidence of the questionnaire. However, due to the nature of this questionnaire, it was judged impossible to present commonly used evidence, so psychometric evidence was not presented. However, as a second option, we tried to secure the rationality of the survey in the process by explaining the process of creating the survey in as much detail as possible.Despite these limitations, the present study provides an instrumental basis for designing clinical studies that reflect the real-world perspectives of patients with LDH by presenting detailed information on their symptoms, disability, and needs. Improvements in back pain, leg pain, sitting, and sleeping were prioritized, and safety, stable treatment effect, and functional recovery were desired. Clinical trials for LDH should be designed to reflect this real-world patient need.As this study was an exploratory survey, the results should be interpreted with caution. We intend to plan a precisely designed registry study including a larger number of patients to overcome the limitations of this survey study and strengthen its validity and generalizability.


In Ethiopia, little is known about postoperative pain trajectories and possible predictive factors associated with them in patients undergoing surgery following traumatic fractures.n = 218). Worst pain intensity was measured with an 11-point numeric rating scale on the first 4 postoperative days and day of hospital discharge. Growth mixture modeling was used to identify subgroups of patients based on their pain trajectories, and logistic regression models to quantify associations between pain trajectories and demographic, clinical, psychological, and life style factors.This multi-center prospective observational cohort study included surgical candidates for traumatic fractures  and consistently high pain . Sub-analysis stratified by cause of injury demonstrated that higher preoperative pain was an independent risk factor for consistently high postoperative pain regardless of the patient’s injury type: traffic accident , machine/tool injury or conflict , or fall . Moreover, longer surgical time was a risk factor for consistently high postoperative pain among patients who had a fall-related injury . In contrast, among patients with a traffic-related injury, receiving a nerve block was a protective factor  compared with general anesthesia.Higher preoperative pain and longer surgical time were associated with a consistently high acute postoperative pain trajectory. Clinicians may use these potentially modifiable factors to identify patients at risk for consistently high pain during the early postoperative period. While several modalities are available for effective management of postoperative pain , 2, modePreviously, pain was expected to be proportional to the extent of tissue damage. However, the biopsychosocial model of pain proposes that patients’ pain experience is a result of extensive modulation of the pain signal through a complex interplay of biological, psychological and social factors, which are unique to each individual . In a meNot surprisingly, the current state of knowledge on acute pain is based mainly on studies from western countries, and their findings cannot necessarily be generalized to populations in developing countries like Ethiopia with less available resources for pain management and different health systems, settings, patient education levels and lifestyles. Furthermore, among the studies conducted in developed and developing countries, different surgical procedures were included but there is a lack of studies within pain after traumatic fracture surgery. Thus, research on the extent of acute postoperative pain and associated risk factors among traumatic fractures surgical populations is of particular importance, primarily given the high frequency of traumatic fractures, in Ethiopia , as wellThis multi-center prospective observational cohort study included surgical candidates for traumatic fractures at two University teaching Hospitals in Ethiopia ; Addis Ababa Burn Emergency and Trauma (AaBET) hospital). AeBET hospital is one of the largest government hospital in the country dedicated to emergency and trauma care, located in Addis Ababa, Ethiopia. Annually, this hospital has ~ 20,000 to 30,000 emergency visits. It is a 129-bed institution with a 52-bed orthopedic ward. The JMC is located in the city of Jimma in southwest Ethiopia. It provides services with a catchment population of over 20 million people. It has a total of 800 beds with 21 clinical service units. The surgery department has about 286 beds; including a 50-bed orthopedic ward.We estimated that a sample of 200 patients would provide adequate power to estimate regression coefficients with sufficient precision with a model including 10 possible predictive factors. To allow for an estimated 10% attrition rate, we aimed to include a sample of 220 patients. With a final sample size of 220, our study had sufficient statistical power to evaluate these potentially predictive factors.Patients scheduled to undergo elective surgery at one of the two study sites from 31 January 2019 through 07 October 2021 were consecutively approached by trained research assistants, who are bilingual speakers of Amharic and Afan Oromo. Patients were approached on the day before their planned surgery and were invited to participate if they met the following inclusion criteria: age 18 years or older, had an upper and/or lower extremity fracture related to injury, fully conscious with no cognitive impairment, and able to communicate in either Amharic or Afan Oromo language. As shown in Fig. Data were collected through patient chart review  and by administering a questionnaire. The adult literacy rate of 51% reported in Ethiopia UNESCO Institute for Statistics, July 2017, many patients could not complete the questionnaire without help. Therefore, we used a face-to-face interviewer-administered questionnaire for all patients . The questionnaire was prepared in the two local languages (Amahric and Afan Oromo) that are predominantly spoken in the study’s settings.On the day before surgery, the following preoperative information was obtained: patient age, sex, education, residence, life style variables , previous surgery, type of injury, and location of injury, as well as preoperative pain, anxiety, depression, and catastrophizing.Intraoperative data, including duration of surgery and types of anesthesia, were collected from the patient’s medical chart on POD1.Postoperatively, ratings of worst pain intensity at the surgical site over the last 24 h were collected on postoperative day (POD) 1, POD2, POD3, POD4, and the day of discharge. These pain ratings were the outcome and were used to determine patients’ acute postoperative pain trajectories.Anxiety and depression were assessed with the Hospital Anxiety and Depression Scale (HADS), a 14-item scale, scored on a 4-point Likert scale (0–3), ranging from “not at all” to “most of the time”. Seven items measuring anxiety and seven measuring depression over the last week yield a total score between 0 and 21 for each subscale . The valPatients’ level of pain catastrophizing was assessed with the Pain Catastrophizing Scale (PCS). The original PCS was developed by Sullivan et al. . It contPatients were asked to rate their level of pain at the surgical site over the last 24 h using the “worst pain” item of the Brief Pain Inventory short form (BPI), which has an 11-point numeric rating scale (NRS) with the end points 0 (no pain) and 10 (pain as bad as you can imagine). The BPI was originally developed as the Wisconsin Brief Pain Questionnaire to assess pain occurrence, intensity, interference with function, pain relief, and pain localization . For thit-tests for continuous variables and Chi-square tests for categorical variables.Categorical variables are reported as counts and percentages, and continuous variables as means and standard deviations. Differences between patients admitted at the two hospitals are assessed using p values was considered significant when p < 0.05. To increase precision of the estimates, we used bias-corrected bootstrapping with 1000 samples. All analyses were considered exploratory, so no correction for multiple testing was performed. Data analyses were performed using the Statistical Package for Social Science (SPSS) version 26 and Stata version 17.The data were analyzed in two steps. In step 1, a growth mixture model (GMM) was fitted to identify subgroups of patients based on similarities in their trajectories of acute postoperative pain across five time points . We identified two distinct trajectories, namely the rapid postoperative pain relief class and the consistently high postoperative pain class. In step 2, the two classes were used as the dependent variable and we fitted a multiple logistic regression model to identify possible associations with pre- and intra-operative factors . Further, we stratified our data by cause of injury and fitted separate logistic regression models. The results are presented as odds ratios (OR) with 95% confidence intervals (CI) and Initially, 220 patients were included and completed the baseline data. Two patients were excluded after self-discharging against medical advice on the day of surgery. Postoperative pain scores were assessed for 218 patients with a retention rate of 99.1% at POD1. Of these, 99.1%, 96.3%, 88.1%, and 99.1% also had pain ratings for POD2, POD3, POD4 and day of discharge, respectively.The demographic, lifestyle, clinical and psychological characteristics of the patients at each hospital are summarized in Table n = 105, 48.2%) experienced moderate pain intensity  on POD1, followed by a rapid decline. Patients in class 2  experienced severe pain intensity  on POD1, followed by consistently high pain intensity over the five postoperative time points. To reflect the pattern of the trajectories, we labeled class 1, “rapid postoperative pain relief" and labeled class 2 “consistently high postoperative pain”.The GMM model based on patients’ pain ratings at five time points during the acute postoperative period identified two classes of patients with distinct pain trajectories. As shown in Fig. Possible predictive factors for membership in the consistently high postoperative pain class are listed in Table With respect to life style, use of khat was associated with reduced likelihood of belonging to the consistently high postoperative pain class; however, this association did not reach the level of statistical significance. Moreover, alcohol users were about 70% less likely to be in the consistently high postoperative pain class compared to non-users.Regarding clinical characteristics, preoperative worst pain intensity was significantly associated with being in the consistently high postoperative pain class. For each unit increase on the preoperative pain intensity scale, the odds of being in the consistently high postoperative pain class increased by 38% . Duration of surgery was significantly associated with higher odds for being in the consistently high postoperative pain. Furthermore, for type of anesthesia, patients with nerve block anesthesia had about 80% lower odds than those who had general anesthesia of being in the consistently high postoperative pain class . Of the psychological factors, only depression remained independently associated with type of pain trajectory. The higher the depression score, the lower the odds of being in the consistently high postoperative pain class .Predictive factors for membership in the consistently high postoperative pain class stratified by cause of injury are shown in Table Type of anesthesia  remained associated with the consistently high postoperative pain class only for those with a traffic-related injury .Duration of surgery was significantly associated with the consistently high postoperative pain class only for those who had fall-related injuries . For each 10 min increase in the duration of the surgery the odds of being in the consistently high postoperative pain class increased by 22%.To our knowledge, this is the first multi-center study on acute pain trajectories in a cohort of Ethiopian patients who underwent surgery for traumatic fractures. We identified two subgroups of patients with distinct trajectories of acute pain: the “rapid postoperative pain relief class” and the “consistently high postoperative pain class” based on five daily pain ratings during the early postoperative period.More than half of the patients in this study were classified as having consistently high postoperative pain, which suggests that acute postoperative pain is a major problem for patients with traumatic fractures in Ethiopia. Postoperative pain management may be a particular challenge in a developing country. Several barriers to postoperative pain management have been identified in previous studies in Ethiopia , 32, sucPatients who had an injury caused by machine/tool use or conflict had an 80% decrease in the odds of having a consistently high postoperative pain trajectory, compared to those with injuries caused by a traffic accident. According to Hu et al. , patientThe subgroup analysis revealed that for patients with traffic-related injuries, receiving nerve block anesthesia was protective against a consistently high postoperative pain trajectory, compared to general anesthesia. This is likely due to the advantage of nerve block anesthesia for postoperative pain management. Several other studies done in Ethiopia , 18, TanThe sub-analysis regression model stratified by cause of injury is unique to this study. Our main finding is that higher preoperative pain was a stable risk factor for having consistently high postoperative pain across all injury types. This finding is consistent with a recent systematic review and meta-analysis, which identified that the presence of preoperative pain is a known predictor for poor acute postoperative pain control . FurtherThis study has several strengths and limitations that need to be considered. The strengths of this study are: prospective multi-center design, the low attrition rate, a relatively representative population that included patients from one of the largest trauma centers and one teaching and referral hospital in Ethiopia, a relatively large sample size and the advanced statistical analysis. Our study has some limitations that should be considered when interpreting the results. The results only apply to patients undergoing surgery for traumatic fractures and do not control for potentially confounding factors such as perioperative administration of analgesia. In addition, several differences were found between the two hospitals with respect to lifestyle-related , clinical  and psychological  factors. The patients admitted to the two hospitals live in different regions of the multi-ethnic Ethiopia, which may result in cultural, contextual, religious, and psychological differences in the patient populations for the two hospitals. While these differences resulted in a more heterogeneous sample, our decision to include patients from two hospitals in two different regions of Ethiopia may have resulted in more generalizable findings.The present study shows two classes of patients based on their acute postoperative pain trajectories, and more than half of patients were classified in the consistently high pain trajectory class. Higher levels of preoperative worst pain intensity and longer surgical duration were significant factors related to the consistently high acute postoperative pain trajectory. Clinicians working at trauma centers should be aware of these factors to identify patients at risk of the consistently high acute postoperative pain trajectory and take measures to minimize early postoperative pain. Nerve block anesthesia was associated with lower risk of a more severe pain trajectory in patients with traffic-related injuries. Clinicians need to be aware of patients with traffic-related injuries scheduled for operative fixation of fractures and consider using a multimodal pain management regiment in line with current guidelines.