Postmastectomy pain is chronic pain that occurs in females after breast surgeries. In this study, we estimated the vertebral levels reached by two different volumes (20 ml and 30 ml solutions) in the erector spinae block (ESB), as well as assess pain improvement and patient satisfaction in females with postmastectomy pain syndrome.Fifty patients were assigned to two groups. The 20 ml group received ESB with 10 ml of bupivacaine 0.5%, 1 ml of 40 mg/ml of methylprednisolone, 2 ml of non-ionic contrast, and 7 ml of saline 0.9%. The 30 ml group received ESB with 15 ml of bupivacaine 0.5%, 1 ml of 40 mg/ml of methylprednisolone, 2 ml of non-ionic contrast, and 12 ml of saline 0.9%.P < 0.001). The T1 to T6 blockade levels were achieved in six patients (24%) in the 20 ml group, versus 23 patients (92%) in the 30 ml group (P < 0.001). The numerical rating scale (NRS) improved in the 30 ml group during the follow-up period, compared to the 20 ml group. The T1 to T6 blockade levels showed better NRS (P < 0.001) and patient satisfaction (P = 0.011) than other blockade levels.The mean numbers of the blockade segments were 5.12 ± 0.726 and 6.36 ± 0.569 in the 20 ml and 30 ml groups, respectively (The injection of a 30 ml solution of 0.25% bupivacaine with methylprednisolone in erector spinae block (ESB) may result in better analgesia and higher patient satisfaction in individuals with postmastectomy pain syndrome (PMPS) compared to a 20 ml solution.ClinicalTrials.gov (NCT05192278) on 14/1/2022. Breast cancer is the most prevalent cancer among women. Postmastectomy pain syndrome (PMPS) is one of the most common postoperative complications that requires effective and safe management . It is aErector spinae block (ESB) is a relatively new technique used to manage acute postoperative pain in different surgeries, as well as chronic pain syndromes. Although its mechanism is not fully understood and most publications consist of case reports and personal clinical experiences, the available data agree on its simplicity and safety compared to bilateral paravertebral blocks or thoracic epidural blocks , 7.ESB can be performed using either the superficial technique, located between the large rhomboid muscles and the erector spinae muscle, or the deep technique, beneath the erector spinae muscle . RecentlIn this study, we aimed to determine the vertebral levels reached by two different volumes (20 ml and 30 ml solutions) in the erector spinae block (ESB), as well as assess pain improvement and patient satisfaction in females with postmastectomy pain syndrome.We conducted a prospective randomized comparative pilot study in the pain clinics of Mansoura University Hospital, Egypt, from January 2022 to September 2022. We obtained approval from the Institutional Research Board (IRB) of the Mansoura University Faculty of Medicine on 28/11/2021 (Code number: R.21.11.1523.R1). The study was registered on Clinicaltrials.gov on 14/1/2022 (NCT05192278) and was conducted in accordance with the Helsinki Declaration. After providing a clear explanation of the study details, we obtained informed written consent from all study participants.The inclusion criteria were as follows: females who had undergone mastectomy surgery more than six months ago, aged over 18 years old, experiencing postmastectomy pain that was not relieved by medical treatments alone , with a Numeric Rating Scale (NRS) score greater than four. Additionally, participants needed to have a body mass index (BMI) of less than 30 and be classified as American Society of Anesthesiology Physical Status (ASAPS) class I or II. The NRS was used to assess and express their pain levels, ranging from 0 to 10, with ten representing extreme pain and zero representing no pain.The exclusion criteria were as follows: patient rejection, systemic or local sepsis, allergy to the medications used in the study, coagulopathy, distorted local anatomy, uncontrolled cardiovascular diseases, neurological deficits, respiratory disorders, psychiatric disorders, or a history of drug abuse.We used the Power Analysis and Sample Size (PASS) software program, version 15.0.5 for Windows 2017, to calculate the sample size. Primary data were obtained from a pilot study conducted in Mansoura University Hospital, which included 12 patients. The primary outcome was the number of vertebral levels reached by the dye. Participants were assigned to either the 20 ml group or the 30 ml group. The number of levels reached was 5.6 ± 1.02 for the 20 ml group and 6.8 ± 1.17 for the 30 ml group, with a difference of 1.2 levels. To achieve 95% power in the proposed study, using a two-sided two-sample unequal-variance t-test with a significance level of 5%, a sample size of 23 patients in each group was required. Assuming a dropout rate of 10%, the number of patients in each group was set at 25.Randomization was performed using a computer-generated list of random numbers in a 1:1 ratio. The distribution results were kept in an opaque envelope by the study administrator. On the day of the block, the study manager provided the envelope to the anesthesiologist who performed the block.n = 25) received ESB with 10 ml of bupivacaine 0.5%, 1 ml of 40 mg/ml of methylprednisolone, 2 ml of non-ionic contrast, and 7 ml of saline 0.9% .The 20 ml group (n = 25) received ESB with 15 ml of bupivacaine 0.5%, 1 ml of 40 mg/ml of methylprednisolone, 2 ml of non-ionic contrast, and 12 ml of saline 0.9% .The 30 ml group , the correlation between the levels of solution spread and pain improvement with patient satisfaction, and the occurrence of any complications during or after the injection.The same anesthesiologist who performed the block assessed the number of vertebral levels reached by the solution and managed any reported complications. NRS scores and patient satisfaction were evaluated by another team member who was unaware of the patients' group assignments.Data analysis was conducted using the Statistical Package for the Social Sciences . The Shapiro–Wilk test was used to assess data normality. Parametric data were expressed as means ± SD, while non-parametric data were presented as medians and interquartile ranges. Categorical variables were reported as numbers (percentages). One-way ANOVA and Kruskal–Wallis tests were used for continuous data, and the Chi-square test was used for categorical data. Bivariate correlations were assessed using Pearson's or Spearman's correlation coefficients as appropriate. A probability (P) value of ≤ 0.05 was considered statistically significant.P > 0.05).Sixty-two patients were assessed for eligibility, and 12 patients were excluded, resulting in a study sample of 50 patients . Additionally, the mean numbers of vertebral blockade were 5.12 ± 0.726 and 6.36 ± 0.569 in the 20 ml and 30 ml groups, respectively (P < 0.001). In relation to the C8 to T6 blockade, six patients (24%) were observed in the 30 ml group compared to none in the 20 ml group (P = 0.009). Regarding the T1 to T6 blockade, six patients (24%) were found in the 20 ml group compared to 23 patients (92%) in the 30 ml group (P < 0.001). Furthermore, 19 patients (76%) and 25 patients (100%) exhibited T2 to T6 blockade in the 20 ml and 30 ml groups, respectively (P = 0.009).Table P < 0.001) .Table No complications were reported in either group during the procedure or the follow-up period.Post-mastectomy pain syndrome (PMPS) is a common problem following breast surgeries, and its prevention and management remain challenging with limited research available .To the best of our knowledge, this study is the first to compare two volumes (20 ml versus 30 ml) of erector spinae block (ESB) in patients with PMPS and assess the levels of dermatomes covered by each volume. We also evaluated the volume that provided the best pain improvement and patient satisfaction in women with post-mastectomy pain.In our study, we found that the 30 ml solution resulted in a greater number of vertebral blockade levels compared to the 20 ml solution. This interesting finding suggests that the larger volume group may have better pain relief and patient satisfaction. This contributes valuable information to the literature and calls for further large-scale studies to confirm our results.The mechanism of action of ESB has been investigated radiologically and anatomically on fresh cadavers. Forero et al. found that ESB spreads to the dorsal and ventral rami of the spinal nerves . Diwan eConsidering the anatomical distribution of thoracic innervation, it is important to note that the areas affected by PMPS receive innervation from different dorsal roots of the spinal nerves. The medial brachial cutaneous nerve arises from C8 and T1 levels and innervates the upper medial aspect of the arm, while the axilla is innervated at the T2 level , 15. TheAoyama et al. compared ESB with 20 ml of 0.5% ropivacaine to paravertebral block for breast surgery and found that the percentage of patients in the paravertebral block group who developed T3 and T5 blockade was higher than in the ESB group .Bang et al. studied the effectiveness of thoracic ESB as analgesia after lung lobectomy and performed the block at the T5 level with a total volume of 30 ml, consisting of a mixture of 15 ml of 0.75% ropivacaine and 15 ml of saline. They observed sensory blockade in the T2-8 dermatomes, with numeric rating scale (NRS) scores of 1 at rest, 3 during active coughing, and 1 during deep breathing .Hasoon et al. reported pain relief for three months in an elderly female with PMPS after ESB at the T5 level using 2 ml of non-ionic contrast, 1 ml of 40 mg/ml of methylprednisolone, and 9 ml of 0.25% bupivacaine [In contrast to our results, Fang et al. stated that ESB with 20 ml of 0.25% bupivacaine alone was insufficient to relieve pain and required additional postoperative sufentanil to achieve effects similar to those of thoracic paravertebral block for patients undergoing thoracotomy. However, they approved that ESB has less frequent side effects .Regarding the reported side effects, Azmy et al. stated that complications of ESB are infrequent because the site of the block is far away from the spinal cord, the pleura, and any major blood vessels . AdditioThe current research is a single-center study with a relatively small sample size, which could affect the study's power. The sample size is relevant to the level of variability and is likely insufficient to clearly determine if PMPS is reduced in these patients.The injection of a 30 ml solution of 0.25% bupivacaine with methylprednisolone in erector spinae block (ESB) may result in better analgesia and higher patient satisfaction in individuals with postmastectomy pain syndrome (PMPS) compared to a 20 ml solution.We recommend conducting large-scale multicenter studies with different validated questionnaires to validate and generalize our findings.


Preoperative knowledge of expected postoperative pain can help guide perioperative pain management and focus interventions on patients with the greatest risk of acute pain. However, current methods for predicting postoperative pain require patient and clinician input or laborious manual chart review and often do not achieve sufficient performance. We use routinely collected electronic health record data from a multicenter dataset of 234,274 adult non-cardiac surgical patients to develop a machine learning method which predicts maximum pain scores on the day of surgery and four subsequent days and validate this method in a prospective cohort. Our method, POPS, is fully automated and relies only on data available prior to surgery, allowing application in all patients scheduled for or considering surgery. Here we report that POPS achieves state-of-the-art performance and outperforms clinician predictions on all postoperative days when predicting maximum pain on the 0–10 NRS in prospective validation, though with degraded calibration. POPS is interpretable, identifying comorbidities that significantly contribute to postoperative pain based on patient-specific context, which can assist clinicians in mitigating cases of acute pain. Almost 50% of patients report severe pain in the first 24 h of surgery4. Uncontrolled pain hinders postsurgical recovery, prolonging hospital stays, and increases mortality and the likelihood of chronic pain6. On the other hand, acute pain is commonly managed with opioids, prescribed to over 80% of surgical patients1; the risk of opioid use disorder, a present public health crisis8, increases with dosage and duration1. The American Pain Society recommends that clinicians individualize courses of treatment for each patient, yet existing assessments are heavily subjective, and many recommendations lack strong evidence9. Computational prediction of postoperative pain can provide quantitative guidance for perioperative pain management, and focus interventions on cases at greatest risk of acute painOf the 51 million patients who undergo surgery each year in the United States4. Previous studies have used logistic regression to predict the likelihood of uncontrolled pain in relatively small cohorts of ambulatory10 and elective11 surgical cases, achieving moderate levels of performance. However, a major limitation of these studies is that they rely upon physician evaluations and patient surveys of anticipated pain13, and thus require human input and reflect the results of human prediction of postoperative pain more so than computational prediction.Existing literature on predicting postoperative pain is somewhat sparse and limited in scope. Only a handful of studies have attempted to compare pain across different procedure types15 set embeddings from CPT and ICD-10 codes and use these embeddings in conjunction with structured EHR data to predict postoperative maximum pain scores on the day of surgery and four subsequent days. We developed POPS in a large, multicenter dataset. Furthermore, we validated the model in a prospective cohort and compared its performance against clinicians’ predictions.In this study, we present a machine learning method, the Personalized post-Operative Pain prediction Score (POPS), for predicting postoperative pain in a wide range of surgeries using information about patients and procedures from commonly recorded preoperative electronic health record (EHR) data. We used neural networks to compute attention-based15, and a densely connected feed-forward network  and Brigham and Women’s Hospital  and Newton Wellesley Hospital (NWH). Baseline demographics of the retrospective cohort encompassing surgical patients from these four hospitals are presented in Table Our retrospective dataset consists of preoperative electronic health record data collected for 234,274 adult patients who underwent surgery between April 1th, 2023, and March 20th, 2023. Baseline demographics of the prospective cohort are presented in Table We conducted a prospective study at Massachusetts General Hospital, in which 365 adult non-cardiac surgical patients were enrolled between February 15Pain scores in the EHR were recorded numerically, or in text form. In our retrospective cohort, 222,374 out of 234,274 patients (94.9%) have at least one numeric pain score; 91,270 (39.0%) have pain strings. Overall, pain strings comprise 432,042 out of 4,925,886 recorded pain scores (8.8%). In our prospective cohort, all 365 patients (100%) have numeric pain scores; 130 (35.6%) have pain strings, and pain strings comprise 541 out of 11,100 recorded pain scores (4.9%). The distribution of recorded pain scores by type is shown in Supplementary Fig. The most frequently observed CPT and ICD-10 codes in our study cohorts are reported in Supplementary Tables The distribution of the number of pain score observations per patient on each postoperative day is shown in Supplementary Fig. 16) and severe pain  between 2.39 and 2.63 points Fig. , and a PFor each hospital in the retrospective cohort, we also trained models using data from only one hospital and evaluated predictions of postoperative pain for those models on test data from the remaining three sites  institutional review board (IRB #2020P000301). Our prospective validation protocol was also approved by the MGH IRB (#2022P002958). Clinicians provided informed consent before participation in the prospective study. Study protocols are further detailed in Supplementary Methods. No deviations from these protocols occurred.A transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD)st, 2016, and March 31st, 2020. We excluded patients admitted to the Intensive Care Unit immediately after the surgery and patients who died during the surgery.Our retrospective study included adult patients who underwent non-cardiac surgery with general anesthesia across two quaternary care academic medical centers, MGH and BWH, and two community hospitals, NSMC and NWH, between April 1th, 2023, and March 20th, 2023. We excluded patients undergoing ambulatory surgery, non-elective surgery, or cardiac surgery. We also excluded patients admitted to the Intensive Care Unit immediately after the surgery and patients who died during the surgery.Our prospective study included adult patients who underwent inpatient non-cardiac surgery with general anesthesia at MGH between February 15Clinicians from the anesthesia team were surveyed at the beginning of each case, and their predictions on expected postoperative pain recorded (Supplementary Methods). We also recorded their role , years of experience , and gender. The research team did not intervene in the clinical management of these patients.We employed data from patient electronic health records, and extracted demographics  and preoperative variables . ICD-10 codes recorded prior to the date of surgery and CPT codes associated with each surgery were also extracted from the EHR, along with outcome data. EHR data for all patients was extracted from the Mass General Brigham (MGB) institutional Enterprise Data Warehouse (EDW) system and analytical platform.From the set of CPT and ICD-10 codes present across all patient records in the retrospective dataset, a dictionary of all codes present in at least 1 in 10,000 records was built, comprised of 5,802 unique codes . For each patient, their set of unique codes present both in the dictionary and their electronic health records was computed.54, although in some cases is reported as strings. In these cases, we converted strings into numeric variables using 6 categories . If multiple pain scores were recorded on a given day for a single patient, the highest value was kept. Since pain scores were extracted directly from the EHR, no blinding was required.The outcome studied were the maximal post-operative pain scores reported by patients on the day of the surgery (Postoperative Day 0), and on the four subsequent days (Postoperative Day 1 through 4). Pain is generally assessed using the Numeric Rating Scale (NRS)15. For each patient, this layer produces a single 256-dimensional vector which represents the information contained within their set of CPT and ICD-10 codes, which we refer to as the set embedding.Set embeddings were computed using a neural network consisting of an embedding layer, which accepts as inputs the indexed set of CPT and ICD-10 codes of a given patient, and computes a 130 by 256 zero-padded matrix representation, where each row corresponds to the embedding of a specific CPT or ICD-10 code , and on four subsequent days (Postoperative Days 1–4).n = 190,014), validation , and test sets . The validation set was used for model selection. Reported performance for the retrospective component of our study was evaluated on the test sets. The prospective cohort (n = 365) was only used for model evaluation. We also developed hospital-specific models, in which models were trained and selected using data from only a single hospital. We also evaluated performance on only the subset of the test set that was drawn from single hospitals.Patients in the retrospective dataset were sampled uniformly at random into training , our training objective function was binary cross-entropy. For continuous outcomes, our training objective function was mean squared error.The training dataset was augmented by duplicating each patient without CPT codes. Without augmentation, the distribution of patients without CPT codes in the training set is limited to patients who underwent uncommon procedures. This impacts the computed impact of CPT codes in Table We defined three hypothetical example patients with demographic information, preoperative variables, and CPT and ICD codes required to compute the POPS Table . PatientAttention weights for each patient’s CPT and ICD-10 codes were computed using our fitted model. The effect of each individual code was estimated for these patients by computing the difference in predicted outcomes for an identical patient with that code removed from their set.55. Williams’ test was used to assess statistical significance of differences in Pearson’s correlation coefficients56. The Wilcoxon rank-sum test was used to assess significance of differences in root mean squared error. Differences in pain score distributions between the retrospective and prospective cohorts were assessed using the Chi-squared test. Differences in distributions of categorical variables between the retrospective and prospective cohorts were assessed using the Chi-squared test. Differences in distributions of normally distributed random variables  were assessed using the t-test. Confidence bounds were computed by bootstrap.Statistical significance of differences in area under receiver operating curves was assessed using Delong’s testPower calculations were performed using G*Power 3.1.9.7 to estimate the minimum number of patients required for our prospective study to identify significant differences in predictive performance between clinicians and our model. We computed the required sample size and parameters estimated from the empirical residual distribution of our model-based predictions of postoperative pain in the retrospective cohort. To estimate the residual distribution of clinician predictions, we computed the residual distribution for predicting the population mean pain for every patient. For a power of 0.90 and an α of 0.05 in a paired signed-rank test of performance between our model and clinician predictions, we estimated a required sample size of 365 patients.Further information on research design is available in the Supplemental MaterialReporting Summary


P = 0.09). In addition, minor hepatectomy did not reduce the incidence of shoulder pain compared with major hepatectomy (P = 0.37). The drainage volume within 2 days after surgery was significantly more in those patients with shoulder pain (P = 0.017). In open surgery, surgical sites involving the right anterior lobe (OR (95% CI) 2.021 , P = 0.029) and right posterior lobe (OR (95% CI) 2.322 , P = 0.013) were both independent risk factors for shoulder pain. Left shoulder pain also occurred in patients who did not receive left lateral hepatectomy. The preventive phrenic nerve block was not suitable for post-hepatectomy shoulder pain. Stronger preventative intervention should be used in those high-risk patients.Shoulder pain frequently follows hepatectomy. However, the influence of surgical procedures on shoulder pain is unclear. In this observational study, patients who underwent hepatectomy were enrolled in Shanghai Cancer Center. Shoulder pain and surgical pain were assessed using the numeric rating scale 2 days after surgery. The incidence of shoulder pain was the outcome of the cohort study. Nested case–control analyses were further applied. Three hundred and twelve patients were finally enrolled in this study. Nested case–control analysis showed that there were no significant differences in the number of surgical segments between the two groups ( The acknowledged mechanism of postoperative shoulder pain is the referred pain resulting from C3–5 nerve roots via the phrenic nerve2. The efficacy of phrenic nerve block (PNB) verified this hypothesis3. Previous studies found that younger age and the application of epidural anesthesia were the independent risk factors for post-hepatectomy shoulder pain (PHSP)5. However, few studies focused on the relationship between surgical procedures and PHSP.Shoulder pain occurs frequently after both open and laparoscopic hepatectomy, which affects the life quality of patients. Post-operative shoulder pain was also associated with respiratory dysfunction8. The location of surgical sites is likely involved in the incidence of PHSP. Furthermore, in liver metastases, scattered tumors often require the resection of multiple segments. To the best of our knowledge, the relationship between the location and number of surgical segments and PHSP has not been investigated.As the liver clings to the diaphragm, surgical procedures may irritate the diaphragm. Hepatectomy is a non-standard surgery. Because of the different sizes and locations, tumors require different types of surgical procedures. The right lobe of the liver clings closely to the diaphragm, whereas the left lateral lobe of the liver is relatively dissociative. Previous studies found that mechanical stimulation (such as catheter and suture), endometriosis, and liver abscess around the diaphragm may cause ipsilateral shoulder painTo fill the gap, we performed this observational study to explore the relationship between surgical liver segments and PHSP. This study may be helpful for the prediction and prevention of PHSP.This prospective observational cohort study was conducted between June 2022 and November 2022. A nested case–control analysis was used to investigate the effect of different liver lobes on the incidence of shoulder pain. This study was approved by the Ethics Committee of Shanghai Cancer Center (No. 1612167-18). All patients signed informed consent. All research was performed in accordance with relevant guidelines.All patients underwent hepatectomy at Shanghai Cancer Center. No patients reported shoulder pain as the first symptom at clinic visits.The inclusion criteria were: (1) Patients who underwent hepatectomy under anesthesia, (2) The American Society of Anesthesiologists Score of I–III, and (3) patients who denied a history of shoulder pain.The exclusion criteria were: (1) persistent use of opioids, (2) multiple organ excision during the surgery, (3) surgery records cannot be recognized, and (4) laparoscopic surgery was changed to open surgery.The protocols of anesthesia and analgesia were determined by attending anesthesiologists. For patients who received epidural anesthesia, an epidural puncture was performed between T6 and T8. A test dose (3 ml of 1% lidocaine) was injected after the epidural catheter was placed. Epidural anesthesia was maintained using 0.25% ropivacaine. For all patients, general anesthesia was induced with propofol, rocuronium, and sufentanil, and maintained with inhaled anesthetics (sevoflurane or desflurane), propofol, and remifentanil. Sufentanil and rocuronium were injected intermittently during the surgery.For patients receiving epidural anesthesia, patient-control epidural analgesia was provided. The formula of epidural analgesia was ropivacaine 300 mg combined with sufentanil 100ug. For patients receiving general anesthesia alone, the formula of intravenous analgesic was sufentanil 100ug combined with flurbiprofen 150 mg (or ketorolac tromethamine 90–105 mg). The total volume of the postoperative analgesia bag was 230 ml. The setting of the analgesia device was as follows: a background infusion of 4 ml/h, a bonus of 4 ml with a lockout time of 20 min.All surgeries were completed by the same group of surgeons. The chief surgeons have more than 10 years of experience in hepatic surgeries. The patient was placed in the supine position if the surgical site was the left lobe of the liver. In the patient whose surgical site was in the right lobe of the liver, a padded cushion was placed under the patient’s waist to provide better exposure to the operative field. Both arms of the patient clung to the body during the surgery. In open surgeries, all incisions were made below the right costal margin. Retractors (Omni-Tract) were used to expose the operative field  were recorded. The surgical records were reviewed by two researchers independently. A surgical specialist was consulted when a difference of opinion arose. The number and the locations of surgical liver segments were recorded. Minor hepatectomy was defined as the resection of less than two liver segments. Shoulder pain and postoperative pain were assessed using a numeric rating scale (NRS) 2 days after the surgery. The investigator (DSL) who assessed the pain intensity was independent of anesthesia management, surgical procedures, and statistical treatment. The peak pain within 2 days (not the time the patient was asked) was recorded. The site of shoulder pain was also recorded. Moderate to severe pain was defined as a pain score ≥ 4.In the cohort, cases were the patients who felt shoulder pain within 2 days after surgery. Controls were the patients denied any soreness or pain around the shoulder.4. We assumed that the incidence of shoulder pain after minor hepatectomy and major hepatectomy was 30% and 50%, respectively. The numbers of the two groups were roughly assumed to be equal. The two-sided Z-Test with unpooled variance was used in the calculation. The significance level of the test was 0.05 was a power of 90%. The minimal sample size was 121 patients in each group. As propensity score matching (PSM) was supposed to be used in this study, we increased the sample size by an additional 25%. Therefore, the final sample size of the study was 302.The sample size was calculated using the software PASS . According to a previous study, the incidence of shoulder pain was 40%Normal distribution was tested by the Kolmogorov–Smirnov test. Continuous data that conformed to a normal distribution were presented as means ± standard deviations. Continuous data that did not conform to the normal distribution were expressed as median (quartile spacing). Categorical data were presented as frequencies (percentages). Continuous data that conformed to a normal distribution were compared using a t-test. Continuous data that did not conform to the normal distribution were compared using the Mann–Whitney test. Categorical data were compared using the chi-square test. A PSM was performed to reduce the bias of confounders. Individual propensity scores were calculated using multivariable logistic regression model accounting for age, gender, the use of laparoscopes, and the use of epidural anesthesia. A 1-to-1 matching was performed to the nearest neighbor methods on the propensity scores with a caliper size of 0.02. The relative ratio (RR) for the incidence of shoulder pain was presented with its confidence interval (CI). The significance threshold was set at 0.05 in all analyses. All statistical analyses were performed using the SPSS .A total of 330 patients underwent hepatic surgeries from Jun. 2022 to Oct. 2022. According to the exclusion criteria, 13 patients were excluded ; 4 patients for receiving associating liver partition and portal vein ligation for staged hepatectomy, 5 patients for changing to open surgery). Five patients were additionally excluded because their surgical records were unidentifiable. Finally, 312 patients were included in the study. The flow chart was shown in Fig. P = 0.017). A greater number of surgical segments was observed in patients with shoulder pain  patients reported shoulder pain within 2 days after surgery. None of the patients reported a relationship between shoulder pain and breathing (or eating). Patients with shoulder pain were significantly younger, and epidural anesthesia was more frequently used among them. After PSM, 109 patients were matched in each group. There were no significant differences in age, gender, BMI, use of laparoscopes, use of epidural anesthesia, bile leakage, surgical duration, and surgical position between the two groups. The drainage volume in the case group was significantly more than that in the control group . There were no differences in the incidence of shoulder pain between the two groups. After PSM, 125 patients were enrolled in each group. There were no differences in those variables except surgical duration (P < 0.001) and drainage volume (P = 0.016) between these two groups. The incidences of shoulder pain and moderate to severe shoulder pain between the two groups did not reach statistical differences. (P = 0.37 and P = 0.54).Without PSM, 312 patients were divided into the minor group (n = 173) and the major group (n = 139). In the minor group, laparoscopes were more frequently used (P = 0.262). Univariate logistic regression analysis showed that the surgical site involving the right anterior lobe (OR (95% CI) 2.313 , P = 0.007) and right posterior lobe (OR (95% CI) 2.477 , P = 0.002) increased the incidence of shoulder pain. Multivariate logistic regression analysis showed that, from the perspective of surgical procedures, surgical sites involving the right anterior lobe (OR (95% CI) 2.021 , P = 0.029) and right posterior lobe (OR (95% CI) 2.322 , P = 0.013) were both independent risk factors for shoulder pain . The baseline data of patients were shown in Table A total of 21 patients received open right hemihepatectomy. Among them, 10 (47.6%) patients reported shoulder pain.The data on the site of pain was shown in Fig. In this cohort study, we found that minor hepatectomy did not reduce the incidence of PHSP. Furthermore, the nested case–control analyses showed that hepatectomy involving the right lobe of the liver was the independent risk factor for PHSP.9. In the comparison of these two groups, minor hepatectomy showed a similar incidence of PHSP. The possible explanation was that even in minor hepatectomy, for a better surgical view, the superior liver border was also mobilized from the diaphragm. The tissue damage during the separation may irritate the diaphragm, which induces PHSP. The comparison of the incidence of shoulder pain showed slight differences before and after PSM, mainly because laparoscopes were performed more frequently in minor hepatectomies. The pneumoperitoneum produced by the laparoscopy can directly cause postoperative shoulder pain in many types of surgeries11. In clinical practice, to reduce surgical trauma, surgeons tend to perform minor hepatectomy using a laparoscopic technique (verified in this study). As a result, minor hepatectomy may cause a higher incidence of PHSP in the clinical observation. Therefore, we suggested that the risk of shoulder pain after minor hepatectomy should be equally valued during the perioperative period.The case–control analysis showed the tendency that more liver segments were resected in the patients who reported shoulder pain. However, the differences were relatively slight and not statistically significant. Minor hepatectomy was defined as the removal of one or two liver segments11. In this study, we found that the drainage volume was significantly more in those patients with shoulder pain, which implied that postoperative hemorrhage may irritate the diaphragm and increase the risk of shoulder pain. However, significant differences were not found in the patients undergoing open surgeries. The possible reasons were: (1) Shoulder pain can be caused by a variety of causes. (2) The sample size was relatively small after we exclude laparoscopic surgeries.As pneumoperitoneum alone may also cause shoulder pain, in the analysis of the risk of specific liver lobes, we excluded laparoscopic surgeries to reduce the bias. In the case–control analysis, we found that surgical sites involved with the right anterior and right posterior lobes were both independent risk factors for PHSP. The most likely explanation was that the right liver lobe was more closely adjacent to the diaphragm. The intraoperative mechanical stimulus directly irritates the diaphragm. Furthermore, the subsequent inflammatory responses around the diaphragm may also contribute to the maintenance of shoulder pain12 found that when hepatic tumors were located adjacent to the diaphragm, radiofrequency ablation caused referred shoulder pain. In addition, most of these patients were found diaphragmatic injuries after CT scans. Lguchi et al.13 also found that in radiofrequency ablation of pulmonary tumors, the patients with tumors near the diaphragm showed higher incidences of shoulder pain. However, in those studies, thermal injury was the primary cause of diaphragmatic injury. Whether intraoperative procedures showed a similar effect has not been verified in previous studies. Another possible explanation was the operative position. The special operative position of the right hepatectomy may overly abduct the shoulder joint. Olumuyiwa et al.14 pointed out that ligament strain and referred phrenic nerve pain contributed to post-operative shoulder pain. However, Miyoshi et al. found that most patients reported right shoulder pain even in a symmetrical position during hepatectomy, which indicated that PHSP is not a type of myofascial pain4. Based on the case–control analysis, we found that the surgical position in our institution did not increase the risk of shoulder pain. Whereas, in the left lateral lobe hepatectomy, the left hepatic vein was relatively easy to expose, which reduce the irritation of the diaphragm during the process. These findings suggested that stronger prevention strategies should be applied in the patients who receive the right hepatectomies.Head et al.3 have reported that PNB was effective in the treatment of PHSP. Previous studies pointed out that PNB during the perioperative period can reduce the incidence of shoulder pain after thoracic surgery and laparoscopic cholecystectomy17. In this study, we found for the first time that left shoulder pain may also occur in those patients who received left medial lobe or right hepatectomy. The left lateral lobe of the liver lies to the left of the medial axis of the diaphragm. These findings indicated that the location of the surgical site did not determine the site of shoulder pain, which suggested that ipsilateral prophylactic nerve block may not be suitable for the prevention of PHSP. This phenomenon may be explained by the hypothesis that during open right hepatectomy, the inferior vena cava serves as a fulcrum. When the right liver is pulled down, it may cause the left lateral lobe to rise and irritate the diaphragm, which ultimately results in left shoulder pain.The treatments of referred shoulder pain can be classified as interventions on pneumoperitoneum, pharmacological treatments, and invasive treatment. Among invasive treatments, PNB was the most frequently used therapy. Bak et al.19. In addition, the effectiveness of opioids in the prevention of referred shoulder pain was controversial20. In the nested case–control analysis, we found that there were no differences in the amount of intraoperative sufentanil between the two groups, which is contrary to the previous study4. Our finding suggested that intraoperative opioids cannot reduce the risk of PHSP. Intraoperative high-dose opioid therapy may increase the risk of postoperative nausea and vomiting21, which was not an ideal means of the prevention of PHSP. Therefore, additional trials were needed to investigate the effect of analgesic drugs in preventing shoulder pain.The difficulty in prophylactic nerve block indicated that pharmacological intervention may be a future direction for the prevention of PHSP. Past studies found that neither pregabalin nor gabapentin was effective in the prevention of referred shoulder painThere were a few limitations in this study. Firstly, specific types of hepatectomies were not included in this study, because it is difficult to categorize liver resections strictly. Secondly, it was a single-center study. All operations were performed by the same group of surgeons. Similar surgical manipulations may cause sample bias. In addition, the surgical positions in our hospital may be different from other institutions. Therefore, the findings in this study need to be further confirmed in future studies in other institutions.In conclusion, minor hepatectomy also showed a high incidence of postoperative shoulder pain. Surgical procedures on the right anterior lobe and right posterior lobe were both independent risk factors for shoulder pain. Stronger prevention measures should be used in those high-risk patients.Supplementary Figure 1.Supplementary Legends.


To evaluate the impact of radiosensitivity on outcomes of spinal metastases treated with stereotactic body radiotherapy (SBRT) and identify the correlated prognostic factors.The authors retrospectively reviewed the records of all patients who underwent SBRT with no prior radiation for spinal metastases between October 2015 and October 2020 at Sun Yat‐sen University Cancer Center. On the basis of radiosensitivity, patients were divided into two groups—radiosensitive and radioresistant. The endpoints included local control (LC), overall survival (OS), pain relief, and time to pain relief.p = 0.02 and p < 0.001, respectively). The presence of other metastases (p = 0.04) and pain at enrollment assessed by the Brief Pain Inventory predicted for worse OS (p = 0.01). The 6‐, 12‐, and 24‐month LC rates were 88%, 86%, and 82%, respectively. Younger age was identified for better LC and pain relief . There was no variable independently associated with time to pain relief. As for toxicity, no Grade ≥3 toxicity was observed.A total of 259 (82.5%) patients with 451 lesions were assessable with a median follow‐up time of 10.53 months. The 1‐, 2‐, and 3‐year OS rates were 59%, 52%, and 44%, respectively. The median survival was 33.17 months. Higher Karnofsky Performance Scale score and shorter time to diagnosis of spinal metastases from primary cancer at consult predicted for better OS (Regardless of radiosensitivity, SBRT is feasible and appears to be an effective treatment paradigm for patients with spinal metastases, with limited accepted toxicities. The definition of pain flare was temporary worsening of pain in the treated site, which maybe a potential side effect of palliative radiotherapy for symptomatic bone metastases.Therefore, this study aimed to assess the influence of tumor radiosensitivity on the effect of SBRT to patients with spinal metastases, and attempt to elucidate indications for patient selection. Further categorizing tumors with different radiosensitivity ,22.1We retrospectively reviewed a consecutive series of 547 lesions in 314 patients who were treated with SBRT for spinal metastases at Sun Yat‐sen University Cancer Center between October 2015 and October 2020, and gathered outcomes until December 2020. All patients had histologically proven primary cancer diagnosis. Spinal metastases were diagnosed by CT and/or MRI and/or PET‐CT. Institutional review board (IRB) approval was obtained at the Sun Yat‐sen University Cancer Center, Guangzhou, China.Eligibility criteria included: age >18 years; a pathological diagnosis of primary cancer; oligometastasis ; KPS score of ≥70; lesions treated with radiographic or clinical follow‐up; a maximum of three separate sites of treatment, up to two contiguous levels within one radiation field. Patients were ineligible if they had acute spinal cord compression or the presence of overt spinal instability.2.2SBRT was performed using intensity‐modulated radiation therapy planning or other dose painting techniques. Unless contraindicated, all patients underwent 3 mm slice thickness contrast‐enhanced CT and/or MRI simulation scanning. Patients received radiation in one to six fractions with a 6–8 MV X‐ray beam applied using the Elekta Precise Treatment System (Elekta AB) or the Elekta Versa HD System (Elekta AB). The contouring guidelines for the targets and organs‐at‐risk, dose delivering and dose restriction of spinal metastases treated with SBRT in accordance with previous studies2.3LC was defined as no progression within the treated vertebral body level on following CT or MRI. Vertebral compression fracture (VCF) was defined as de novo and progressive preexisting fractures. Toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.2.4A retrospective review of the hospital records and radiographic studies of these patients was performed. Data on each patient including age, sex, date of initial diagnosis of primary cancer, histology of primary cancer, date of diagnosis of first spinal metastasis, location of the spinal metastasis , radiation sites, other metastases , further radiotherapy to other sites, the presence of paraspinal extension, further systemic treatment, number of the spinal metastasis, previous treatments  and KPS score, pre‐SBRT pain as assessed by the BPI (when available), ESCC grade pre‐SBRT, and SBRT information  were gathered.2.5p‐values were two‐sided. Here, a p < 0.05 was considered statically significant. Statistical analysis was performed using SPSS software .Both continuous and categorical variables were summarized. The Kaplan–Meier product‐limit method was used to estimate OS, and survival curves were compared using the log‐rank test. Factors associated with OS after SBRT were assessed using univariate and multivariate Cox proportional hazards analyses, as well as LC. Hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were computed. Factors associated with pain palliation and the incidence of SBRT complications were assessed using univariate and multivariate logistic regression analyses. Factors associated with the time of pain palliation were assessed using linear regression. All mean values are presented as mean ± standard error. All 33.1During the study period, 314 patients treated with SBRT were included between October 2015 and October 2020, and 55 patients have been lost to follow‐up. The demographic, tumor, and treatment characteristics of 259 patients with 451 lesions are summarized in Table n = 66), followed by prostate cancer (n = 66) and others. The ESCC grades were 0 in 186 (71.8%), 1a in 8 (3.1%), 1b in 31 (12.0%), 1c in 9 (3.5%), and 2 in 25 (9.6%). Of the 24 patients with epidural disease compressing the spinal cord (Bilsky Grade 2), 12 underwent surgery. Because of the medical comorbidities and intolerance for surgery, the other 12 patients were treated with SBRT alone. The spinal metastases with paraspinal extension were 82 (40.59%). One hundred sixty‐two (62.5%) patients experienced prior chemotherapy, and 156 (60.2%) prior bisphosphonate therapy. Patients treated with radiation therapy on other sites were 73 (28.2%). In this consecutive series, 137 (30.4%) lesions were from radiosensitive tumors, 341 (69.6%) from radioresistant malignancies.Among all treated lesions, 27 (10.4%) were cervical, 129 (49.8%) thoracic, 86 (33.2%) lumbar, and 17 (6.6%) sacral. There were 258 patients defined as oligometastases. The most common lesions treated were metastatic tumors of the lung . Of the 451 lesions, 40 (15.4%) were treated with SBRT postoperatively. The median total dose delivered was 30 Gy , with a median fraction number of 5 . The median biologically effective dose delivered was 48.0 Gy .3.2p < 0.001). There was no statistical significance in radiosensitivity (p = 0.12)   , the presence of other metastases (p = 0.04), treating site (p = 0.02), and the presence of pain at enrollment (p < 0.001). On multivariate analysis, KPS score (p = 0.04), treating site (p = 0.04), the presence of pain (p = 0.02), and other metastases (p = 0.02) were significant factors of worse OS  to be prognostic for better pain relief. On multivariate analysis, age retained its significance in terms of pain relief (p = 0.04). The others were not significant factors, including treating site, paraspinal extension, KPS score at consult, the number of metastases, dose, fractions, time to spinal metastases, Bilsky grade, and use of surgery. The median time to pain relief was 0.8 months . On univariate and multivariate analyses, there were no significant factors with time to pain relief.Of the 143 patients with baseline pain, 8 patients were lost to follow‐up and 135 patients were assessable. Because of the retrospective characteristic of our study, it was hard to avoid several patients not to keep up with the follow‐up. The range “0” of time to pain relief means that the patients attained pain relief on the day of radiation. Almost at the time of receiving radiation, pain palliation was achieved. We reported a 76.3% (103/135 patients) of pain relief. Univariate analysis identified age  patients, immunotherapy in 43 (13.69%) patients, and targeted therapy in 105 (33.44%) patients. Obviously, almost these treatments were for primary cancer. In addition, other local treatments were applied, including surgery in 8 (2.55%) patients and radiation for other sites in 66 (21.0%) patients. Meanwhile, 156 patients (49.68%) were receiving bisphosphonate. Bisphosphonates were mainly used in reducing the incidence of bone disease, bone pain, and fracture.3.6p = 0.045). There was no statistically significant difference for radiosensitivity (p = 0.39). On multivariate analysis, the use of bisphosphonate was a predictor for the occurrence of VCF (p = 0.02). Two patients experienced pain flare after SBRT that required hospitalization. Grade 1/2 toxicity consisted of fatigue during treatment for nine patients, and one patient had decreasing smelling after SBRT not requiring treatment. No patient had persistent or worsening neurological symptoms.All patients tolerated SBRT well with minimal complications or toxicity, with no Grade ≥3 toxicities observed in any patient. And there were no cases of myelopathy or radiculopathy. Overall, 26 (8.28%) patients experienced VCFs. Of these patients, two were surgically stabilized before SBRT, with 24 VCFs occurring after SBRT in the nonsurgical sites. Twenty‐one of 26 were de novo VCFs and others were the progression of an existing VCF. On univariate analysis, the factor that significantly affected the rate of VCF was use of bisphosphonate . According to above studies, we can think that SBRT could provide durable local tumor control regardless of radiosensitivity. Of the 28 patients regarded as local failure, liver cancer and renal cell cancer take up 21.4%, respectively. As for LC, we reported that age was a statistically significant factor (p < 0.001). Younger seemed to have a better local tumor control. In future patient selection, age could be taken into consideration.In our study, of patients with radiographic follow‐up, 1‐year LC rate was 86%. The result was consistent with several previous analysis.We also paid attention to the survival outcomes. We reported that the OS rates at 1‐ and 2‐year were 59% and 52%, respectively. These results are consistent with prior reports in the literature.p = 0.02). With better general condition, patients with spinal metastases would accomplish the treatment and gain the survival benefit from SBRT. Moreover, the presence of other metastases and pain at enrollment were significant factors for OS . In those who experienced pain at enrollment, achieving pain relief could be a predictor for better OS (p < 0.01). As is known to us, for bone metastases, including spinal metastases, the most common symptom was pain. Therefore, with regard to patients with baseline pain, timely and optimal analgesia treatment modality was critical before SBRT. Of course, both analgesics and radiotherapy produced analgesic effects. But there was no denying that we did see better OS among patients who had attained pain relief. In the meanwhile, after the diagnosis of primary cancer, regular physical examination is essential in case of the occurrence of spinal metastases (p < 0.04). It demonstrated that treating site was a significant factor for OS (p = 0.02). Overall, it indicated that cervical vertebrae had a better OS (27 patients), followed by lumbar vertebrae (86 patients), thoracic vertebrae (129 patients), and sacral vertebrae (17 patients). It may be because sacral vertebrae are adjacent to ilium. Therefore, some patients developed myelosuppression after radiation therapy. Through the statistical analysis, there was no significant difference found in radiosensitivity with LC (p = 0.12) and OS (p = 0.11). It could be predicted that spinal SBRT provides a satisfying LC and OS, regardless of radiosensitivity.KPS score was used to evaluate general condition of patients. Obviously, higher KPS score, and better general condition. It is regarded as a predictor for OS (p = 0.04) to be a prognostic factor for pain relief. Younger age could achieve better pain relief. In a way, it may be associated with faster cell proliferation in younger people. When selecting patients to be treated with SBRT, age might be taken into consideration.For these patients, SBRT aims to achieve the pain palliation and delay or even prevent the retreatment. We reported 76.3% of pain relief rate, similar to previous reported rates.To our knowledge, there are no uniformly accepted indications in patient selection for spinal SBRT. The above factors might provide instructions in selecting patients. Moreover, the neurologic, oncologic, mechanical, and systemic (NOMS) frameworkp = 0.045) could decrease the risk of VCF. Therefore, it is necessary to take some preventive measures to avoid the occurrence of VCF after SBRT.The most common toxicity for spinal metastases treated with SBRT was the occurrence of VCF. For patients, VCF would have an influence on the quality of life, such as intolerable bone pain. Hence, fracture prevention is of great importance. As for the toxicity of patients treated with SBRT, we demonstrated a risk of VCF of 8.28%, which is consistent with previous spinal SBRT literatures reporting rates ranging from 5% to 42%.Several strengths of this study deserve mention. First, we categorized tumors with different radiosensitivity. No statistically significant difference was found in radiosensitivity with OS, LC, pain relief, and time to pain relief. Our results might provide a reference for future research. Second, in the study, we analyzed the aspects including OS, LC, pain relief rate, and time to pain relief. Obviously, it included and analyzed comprehensive outcomes. Third, without limited in single fraction, we reported one to six fractions; the results were consistent with previous studies. Moreover, to the best of our knowledge, our study was the first to report the outcomes of spinal metastases treated with SBRT in China. There were a number of limitations in this study. Given the retrospectively collected data, selection biases inevitably existed. Furthermore, assessment of pain response was not prospectively collected. The study is limited because of the experience of single institution, which is needed to be validated in other institutions.5In conclusion, regardless of radiosensitivity, SBRT is a noninvasive intervention that seems to be viable, safe, and effective for patients with spinal metastases. With minimal accepted toxicities, a good tumor control was achieved. Furthermore, patients can be expected to develop durable LC and pain relief on treated lesions. To confirm late toxicities and define patient selection, further studies with large sample sizes and a longer follow‐up are required.Lanlan Guo: Data curation (lead); formal analysis (lead); methodology (lead); resources (lead); software (lead); writing – original draft (lead). Qing‐Qing Xu: Investigation ; methodology ; resources ; software ; writing – original draft . Lixin Ke: Conceptualization ; methodology ; resources ; software ; writing – original draft . Ziwei Wu: Data curation ; formal analysis ; methodology . Ziyi Zeng: Formal analysis ; software ; validation . Lei Chen: Methodology ; project administration ; supervision . Yuan‐Yuan Chen: Methodology ; project administration ; supervision . Li‐Xia Lu: Methodology ; project administration ; supervision ; writing – review and editing .The authors have no conflict of interest to declare.The study was approved by the ethics committee of Sun Yat‐Sen University Cancer Center (number SL‐B2021‐237‐01).


The literature shows effective physiotherapeutic techniques for PD in the short term, which do not act on causes and have limitations. The TTNS technique can be used in transcutaneous and percutaneous modalities, with similar effectiveness, but the transcutaneous causes less discomfort. TTNS modulates pain, and long-term benefits could be achieved at low cost and without patient discomfort.Primary dysmenorrhea (PD) is a painful menstruation that can persist for the duration of a woman’s fertile life. Non-steroidal anti-inflammatory drugs, hormonal therapy, physiotherapy techniques, etc., are the main treatments. The main objective of this study is to evaluate the effectiveness of transcutaneous posterior tibial nerve stimulation (TTNS) in PD patients. The study will consist of a single-blind randomized clinical trial, parallel-assigned with two arms. Women with PD (18–43 years) with regular menstrual cycles and at least 4 points in VAS will be randomly divided into experimental (TTNS) and placebo (simulated stimulation) groups during 12 treatment sessions (1 session/week) and several follow-ups: monthly during treatment and 1, 3 and 6 months after. Maximum and mean pain intensity, pain duration, pain severity, number of anti-inflammatory drugs, quality of life, sleep quality, overall improvement, treatment satisfaction and secondary effects will be measured once a month every 6 months and at 3 and 6 months. The Student’s  Primary dysmenorrhea (PD) is a painful menstruation that usually begins six to twelve months after menarche and can remain throughout the fertile life of women, and is generally associated with a normal ovulatory cycle and without pelvic pathology ,2,3,4.PD affects approximately between 45–95% of women; however, a high prevalence has been found in adolescents and young women (16–25 years old) ,5. It isThe current PD pathogenesis is mainly related to an excessive release of prostaglandins by the endometrium into menstrual fluid. Prostaglandin F2 alpha (PGF2α) and natural prostaglandin E2 (PGE2) induce vasoconstriction and contractions of the myometrium. High levels cause uterine hypercontractility that triggers hypoxia and endometrial mucosa ischemia. This uterine hypercontractility together with hypoxia and ischemia could be the cause of the cramp-like pain in PD. It also has associated systemic symptoms with vasopressin (uterine flow reduction), local factors (cervix stenosis) and, sometimes, psychological factors ,6,8.Primary dysmenorrhea is commonly described as cramping (cramping or spasmodic pain) or aching or dull aching . The pain is commonly localized on the lower abdominal or suprapubic region, with or without radiation to the lower back, medial thigh or upper legs. It can start a few hours before or after menstrual bleeding onset, lasts approximately 48–72 h, and is most severe during the first or second day of menstruation ,6,7,8. IPharmacological treatment is based on non-steroidal anti-inflammatory drugs (NSAIDs) and hormonal regulation  ,3. TheseIn addition, there are various physiotherapy treatments for PD pain which do not appear to have adverse effects and are usually well tolerated by patients; they include transcutaneous electrical nerve stimulation therapy (TENS) ,14,15, mIn recent years, a novel technique has emerged that could be aimed at the treatment of uterine hypercontractility, in addition to reducing pain. This technique is called transcutaneous posterior tibial nerve stimulation (TTNS), which consists of a peripheral neuromodulation where the posterior tibial nerve is electrically stimulated above the medial malleolus. This technique was first described by McGuire et al. in 1983 for incontinence treatment using two transcutaneous electrodes, one on each leg . In 1999The technique action mechanism in urological dysfunctions could be the modulation of reflex pathways, rebalancing the inhibitory and excitatory impulses that control bladder function at the spinal cord level ,32. DiffThere are no specific studies that treat PD using TTNS in the literature. Physiotherapists have tools for chronic pain management and health promotion, having skills to perform PD interventions ,21.The posterior tibial nerve (L4–S3) has the same medullary levels as the hypogastric sympathetic plexus (L4–L5) and the pelvic parasympathetic plexus (S2–S4). Its stimulation produces impulse rebalancing in these centers, as is the case with the posterior tibialis relationship with the voiding centers ,37. ThroThe main objective of this study is to verify whether posterior tibial nerve transcutaneous stimulation improves pain, quality of life and sleep deficiency in patients with PD in the short, medium and long term.To prove the Effectiveness of TTNS Treatment for PD in the Short, Medium, and Long TermTo evaluate TTNS effectiveness in reducing NSAIDs in the short term.To evaluate TTNS effectiveness in reducing pain in the short term.To evaluate TTNS effectiveness in improving the quality of life of women with PD in the short term.To evaluate TTNS effectiveness in improving sleep deficiency among women with PD in the short term.To confirm if any decrease in pain is maintained over time.To confirm if any improvement in quality of life is maintained over time.To confirm if any improvement in sleep deficiency is maintained over time.To evaluate patient satisfaction with the treatment.To explore adverse reactions arising from the treatment.The Application of TTNS Results in Decreased Pain during Menstruation, and An Improvement in Quality of Life and Sleep DeficiencyTTNS influences the nerve centers producing a modulation of reflex pathways, thus rebalancing the inhibitory and excitatory impulses that control painful uterine afferents.TTNS modulates A-delta and C-afferent fibers, which reduces pain sensation in the short-medium term and is maintained 6 months after treatment.This is an experimental study, a single-blind randomized clinical trial with a parallel assignment study with 2 arms, which will be implemented in a physiotherapy center.The study will consist of four parts:First interview. The study characteristics will be explained to the participants in a 30-minute interview. A signed informed consent document and a filled-in medical history sheet will be required to participate. This medical history sheet will be filled out by the participant with the support of the researcher during this first interview. It will consist of the following sections: demographic characteristics, life habits, general medical history, gynecological history, obstetric history, menstrual history and history of menstrual pain.Evaluation phase. Several questionnaires during two consecutive menstrual periods will be filled out. These questionnaires will be given to the participants at the first inter-view and they will have to self-administer them during the following two menstrual periods. The objective of this phase will be to know the baseline status of the participants with respect to the variables studied.Intervention phase. Participants included in the study will be randomly assigned to two groups, an interventional and a control group, at a 1:1 ratio. Participants will not know which group they belong to. One session a week (12–30 min) will be conducted. Both groups will receive a symmetrical biphasic current in different leg locations. The stimulation will be performed transcutaneously through two/four electrodes at the leg. The technique shall be always painless, without harmful effects. Patients must fill in the questionnaires and on the last day of the treatment a treatment satisfaction scale will be requested. These questionnaires will be self-administered. The satisfaction and global improvement scales will be completed on the last day of treatment in the office, but on an individual basis, without the advice of the researcher. In addition, after each treatment session, participants will fill out a side-effect questionnaire.Re-assessment phase. The same questionnaires will be filled in a month after treatment, and 3 and 6 months after the treatment ends. In addition, at the end of the 6-month follow-up period, patients will be asked to fill out the adverse effects questionnaire and the satisfaction and global improvement scales again. All these questionnaires will be self-administered.It is estimated that the study will have a sample of 60 participants . The inclusion criteria for participant selection will be the following: women aged between 18 and 43 years, who have regular menstrual cycles (21–35 days) and who present between 4–10 points of the visual analogue scale (VAS) during half of their menstrual cycles per year and/or during their last three cycles for pain located at the suprapubic area, abdomen, lower lumbar area, perineum and/or medial side of the thighs in the first two days of their menstrual cycle.The exclusion criteria established will be: women with an intrauterine device implanted or women with hormonal treatment; those diagnosed in the last 18 months of secondary dysmenorrhea by their gynecologist ; abdominal or pelvic surgeries during the study or having given a birth in the last 6 months; presence of skin lesions such as scars, erosions, etc., on the upper-internal face of the ankles; pregnancies; and women who have pacemakers, uncorrected coagulopathies, severe comorbid disorder, cancer (in the last 5 years or currently), severe mental disorders or lower-extremity neuropathies and physiotherapy treatments for this pathology one month before the study onset.The following variables will be assessed during the study implementation.Maximum and mean pain intensity and pain duration: The visual analogue scale (VAS) will be used. It consists of a horizontal line of 10 cm: on the left is the absence or lesser intensity of pain, with 0: “no pain” and on the right the highest intensity, with 10: “the worst pain imaginable”. The patient will be asked to mark on the line the point that indicates the pain intensity that she feels. To know the score, the researcher will measure the distance from “no pain” to the patient’s mark ,39,40. T®) will be used. The questionnaire has three parts: the pain rating index; a sensory subscale with 15 items that are classified on an intensity scale where 0 = none, 1 = mild, 2 = moderate and 3 = strong, which ranges from 0 to 45 points; a VAS (ranged from 0 to 10); and the current pain index . The higher the SF-MPQ® score, the greater the pain severity [Pain severity: The McGill Short Questionnaire  will be used [The SF-36v2 be used ,43. The ®) will be used. It is a self-administered questionnaire that consists of 19 items in addition to 5 questions for the bed partner. The latter are used as clinical information, but do not contribute to the total score of the index. The 19 items analyze different determining factors of sleep quality, grouped into 7 components: sleep quality, latency, duration, efficiency, disturbances, use of sleep medication and daytime dysfunction, where each component is scored from 0 to 3. The sum of the 7 components gives the total score of the PSQI®, which ranges between 0 and 21 points: the higher the score, the poorer the sleep quality [The Pittsburgh Sleep Quality Index . The questionnaire consists of 7 items. The patient must choose the one that most closely approximates the improvement obtained with the treatment. The higher the score, the worse the impression of change . The patAs a subjective measure of the success of the treatment, patients will be asked, using a Likert scale, if they would like to continue with the treatment to maintain the objectives achieved. The scale shows the degree of agreement or disagreement with the treatment. The patient should fill it in at the end of the treatment and at the end of the reassessment. It will be measured at 5 and at 11 months.Possible treatment adverse reactions will be collected, and patients will be asked to fill in a short questionnaire prepared by the investigator after each treatment session. Time frame: Once a week for 12 weeks during treatment and a follow up 11 months after the onset.The procedure of the study will be established in two arms.® PelviTone stimulation device. The stimulation range will be selected according to the tolerable pain limit for the patient, between 1 and 30 mA (adjustable in 1 mA levels). An intensity elevation will be allowed each time the patient perceives the fading of the previous sensation due to accommodation. Under no circumstances should the stimulation cause a painful feeling.TTNS group. Participants will receive an intervention session each week over a period of 12 weeks. The total application time will be 30 min. A symmetrical biphasic current will be applied, with a frequency of 20 Hz in continuous mode and an impulse duration of 200 μs. Participants will be placed in the supine position with the soles of the feet together and the knees flexed and abducted at 90°. Two adhesive electrodes will be used for each leg. The first will be 32 mm in diameter and placed on the posterior tibial nerve, 4–5 cm cranial to the internal malleolus, between the posterior edge of the medial border of the tibia and the soleus tendon. The second will be 50 mm × 50 mm and placed in the ipsilateral calcaneus. The electrodes will be connected to a NeuroTracOne intervention session per week will be performed during a 12-week period time. The total application time will be 30 min. A discontinuous current at 2 Hz frequency and a pulsed frequency of 50 μs, with 2 s of work and 10 s of pause will be applied in other localization. The participant will be placed in the same position. Two 50 mm × 50 mm adhesive electrodes will be placed on the external face of the thigh, on a single leg. This area is outside the territory of the posterior tibial nerve. This simulated current is considered to be insufficient to achieve therapeutic effects in the body and to be outside of the usual ranges. The pain limit level of the patient will be considered for graduating the intensity . Patients will experience a low or moderate sensation and no muscle contraction will be achieved.The data will be collected through self-administered questionnaires. These data will be randomized using the SPSS v26 software .For the statistical analysis, the corresponding statistical tests will be carried out to establish the differences between groups and differences within each group independently. t-test for independent samples or a Mann–Whitney U test as appropriate. Qualitative variables will be analyzed using an x2 test. The relationships of the quantitative variables to each other will be tested using the Pearson or Spearman correlation as appropriate. To analyze the effect of the intervention, the results obtained among the intervention group will be compared with those obtained among the control group. A value of p < 0.05 will be established as statistically significant.The results will be expressed as mean ± standard deviation for the quantitative variables and as a number and percentage for the qualitative variables. Normality will be evaluated with the Kolmogorov–Smirnov test. The mean of the two groups will be compared using a Student’s ClinicalTrials.gov, accessed on 21 May 2023, registration number ID: NCT04896814.The study was approved on 12 December 2019, by the Ethics Committee for Drug Research, Valladolid East Health Area, of the Hospital Clínico Universitario de Valladolid, located at Hospital Clínico Universitario de Valladolid, Av. Ramón y Cajal, 3, 47003 Valladolid (Spain). The research will follow Helsinki and CONSORT guidelines and all participants will be informed and sign an informed consent to participate. The study has a Dysmenorrhea is currently postulated as one of the health problems that most affect the quality of life of women, with repercussions on their working life. In addition, physiotherapy is very present today and treatments are emerging with the aim of improving pain and the quality of life of patients with urogynecological complications ,32,46.There are numerous studies in the literature about physiotherapy treatments which try to relieve menstrual pain ,17,21,22However, many limitations have been found in the reviewed publications, with low methodological quality. Likewise, it is observed that the treatment techniques used in these studies have been proposed to combat pain secondary to the underlying pathology and not to the cause itself, obtaining short-term results ,13,21.Posterior tibial nerve stimulation has been studied as a treatment for chronic pelvic pain with beneficial results in reducing pain and improving quality of life ,33,34,35In these studies, middle-aged men and women with a diagnosis of chronic non-cyclic pelvic pain of more than 6 months’ duration, in which PD was not found, were included. Although PD is considered a chronic pelvic pain, it is necessary to differentiate it from other non-cyclical pathologies such as endometriosis, interstitial cystitis, etc. Most of the intervention groups consisted of 12 weeks of treatment at the rate of one 30 min session per week of percutaneous application, inserting the needle 3–6 cm cephalad from the medial and posterior malleolus to the tibia bone and with a neutral electrode placed in the same leg in the plantar arch of the foot, by unilateral application. Stimulation parameters of 20 Hz frequency and 200 µs pulse duration and intensity at the motor contraction threshold were used. In the present study, the same application modality will be used, although it was decided to perform it bilaterally in order to increase the therapeutic effects and by transcutaneous application. The technique has been used over time in two variants, transcutaneous (using surface electrodes) and percutaneous (using needles). Most studies have used the percutaneous modality, but other studies have demonstrated similar transcutaneous modality effectiveness, with a discomfort reduction that patients feel when being stimulated ,49. All Finally, no studies addressing the treatment of PD using this technique have been found.The sample required to carry out the study requires very specific inclusion and exclusion criteria, which could limit the planned sample size.Although it is not the aim of the present study there are no tools for measuring the rate of prostaglandins or uterine contractility.The technique of transcutaneous stimulation of the posterior tibial nerve in its percutaneous modality could be considered as an alternative treatment for primary dysmenorrhea without adverse effects for women. This technique could be a useful, effective and safe tool for the treatment of women with primary dysmenorrhea improving pain, quality of life and sleep, and reducing work absenteeism.


Background: In primary healthcare settings, chronic low back pain (cLBP) is a widespread health issue with a great global impact.Methods: A cross-sectional analytical study was performed on 918 adults attending primary healthcare settings in Makkah, Saudi Arabia, to estimate the cLBP prevalence, its effect on health-related quality of life (QOL), and predictors of subsequent disability. The visual analog scale of pain (VAS), World Health Organization Quality of Life Scale (WHO-QOL), and Oswestry low back pain disability index (ODI) were used to assess back pain severity, impact on QOL, and physical disability, respectively.Results: The prevalence of cLBP among adults attending primary care settings in Makkah City was 25.9%, and 88.6% of them had a limited range of motion of the spine. About 58.1% had abnormal radiological findings detected by MRI. Based on the VAS scale, most patients (83.8%) had mild pain. The median (IQR) QOL score was 70 (60-80). Minimal and moderate disability scores were prevalent among 16.2% and 65.7% of patients, respectively. Disability scores were independently predicted by a lower QOL score  and higher VAS scores . Furthermore, disability was independently associated with having post-void residual volume (PVRV)  and abnormal X-ray findings .Conclusion: cLBP is common among adults attending primary care settings in Makkah City; it is associated with moderate disability and lower health-related QOL. Low back pain (LBP) continues to be a major health problem. Despite the significant advances in diagnostic modalities, identifying the specific cause of LBP continues to be challenging . The terChronic LBP (cLBP) has been considered a common longstanding problem in the primary healthcare setting, with a significant burden in developed and developing countries. It may lead to long-term disability, economic loss due to decreased work hours, and frequent healthcare service use ,5. Low hThe severity of back pain can be assessed by using various measures , and itsThis study aims to examine the prevalence of cLBP among adults seeking medical services in primary healthcare settings in Makkah City to evaluate the association of cLBP on HRQOL and to determine the predictors of subsequent disability among these patients.A cross-sectional analytical study was performed to estimate the cLBP prevalence, its effect on HRQOL, and predictors of subsequent disability among adults attending primary care settings in Makkah City. The sample comprised patients who had attended outpatient primary healthcare centers seeking medical services from January 2023 to April 2023.The study was conducted in Makkah, a city of great religious significance in Islam and a prominent location in the western region of Saudi Arabia. Consequently, there exists a significant variation in the social, cultural, and educational backgrounds of the population. The city has a population of over two million individuals, who are distributed among 60 distinct districts. The placement of primary healthcare centers (PHCCs) is determined by residential communities. The health authorities have implemented a division of Makkah City into four distinct areas, namely, north, east, west, and south. Sampling and randomization procedures were conducted in accordance with the distribution of PHCCs. A total of 10 accredited PHCCs from all four districts were first selected in a random manner from the list of PHCCs located in the specified area. Subsequently, patients were selected equally from each center by using systemic random samples from the selected PHC centers until the required sample size was reached.The calculated sample size was n = 765; after adding 20% dropout, the final sample size was 918 subjects using the common formula for cross-sectional studies for 46.4% prevalence of low back pain, with a 5% margin of error, and 95% confidence interval (CI) and two for the design effect . PatientInclusion criteria for further assessmentWe included all adults (18 years and older) complaining of activity-related LBP for more than 12 weeks due to intrinsic spine causes , with or without radicular symptoms .Exclusion criteria from further assessmentFurther assessment excluded patients who were pregnant, patients with intra-pelvic pathology that is thought to be the cause of referred pain to their lower back, patients with osteoporosis documented by bone mineral density (BMD) and dual-energy X-ray absorptiometry (Dexa scan), patients with inflammatory back pain as ankylosing spondylitis or other seronegative spondyloarthropathies, and patients with any other autoimmune diseases that may affect the spine as confirmed by blood work and imaging studies. In addition, patients with a current or past history of tumors, previous surgery, or significant trauma to the spine were excluded.Clinical evaluationAll selected patients were subjected to detailed history taking, including the onset, course, duration, and nature of the pain ; other associating symptoms denoting systemic affection; history of osteoporosis; other autoimmune diseases; and previous trauma of the spine. Neurological history taking (motor weakness or sensory affection of both lower limbs or bowel and/or bladder incontinence) was also performed.In addition, patients were subjected to a thorough physical examination, focusing on the examination of the spine . We examined the spine’s range of motion (measured by a bubble goniometer) and forward flexion (measured using Schober and modified Schober tests), side-bending, and rotation, in addition to carrying out the occiput-to-wall distance test to exclude inflammatory back pain. Further, patients were subjected to a full neurological examination of both lower limbs . This examination included straight-leg raising and crossed-straight-leg raising tests (SLRT), to check for sciatica and lower lumbar nerve root irritation, and femoral stretch tests (FST), to check for upper lumber nerve root compression. Finally, a detailed abdominal examination was also conducted to exclude any referred pain from internal organs.The severity of back pain was assessed using the visual analog scale of pain (VAS), a horizontal, straight, fixed-length indicator line (100 mm). The left end of the scale, 0, represents no pain, while the right end, 10, represents the worst suffering experienced. Patients make an indentation on the indicator line at the location that best captures their impression of the pain. Then, the VAS score is calculated using a ruler and measuring the distance in millimeters (mm) between the left end of the line and the patient’s marked point. The measured distance yields values between 0 and 100, with a higher number denoting more intense discomfort. The range from 0 to 4 mm denotes no pain; 5-44 mm, mild pain; 45-74 mm, moderate pain; and 75-100 mm, severe pain.Questionnaires used in the studyA semi-structured questionnaire was designed to collect the following data from the patients:· Socio-demographic data: age, gender, education, occupation, residence, marital status, and economic level· Health data: past and health-seeking behavior risk factors and family history· Clinical data on back pain: onset, course, duration, previous management, complications, neurological manifestations, and data on current radiological evaluationThe WHOQOL-BREF questionnaire, which is derived from WHOQOL-100 and abbreviated and validated, was used to evaluate back pain’s impact on HRQOL. This tool includes 26 questions to evaluate overall QOL and its specific domains . The QOL tool is scored from zero to 100. The greater the score in each domain, the better the QOL. Zero is considered the least desired QOL score, while 100 is the most desired.The modified Oswestry low back pain disability index, which has been widely used to assess functional status in LBP, was used to assess physical disability. The cLBP disability scores were classified as follows: minimal (0-20%), moderate (21-40%), severe (41-60), crippled (61-80%), and bedridden (81-100%).Radiological evaluationPlain radiographs of the lumbosacral spine  were taken for all the patients to search for any pathological causes of their symptoms. A lumbosacral spine MRI was also carried out to detect any pathoanatomical lesions not apparent by plain X-ray or to confirm the findings of conventional radiography when they did not match the clinical findings of the patient. All the radiographic images were analyzed by a radiologist who was completely blinded to the medical history and physical findings of the patients.Laboratory evaluationAcute phase reactants (ESR and CRP) were performed for all the subjects to exclude the presence of any inflammatory element causing their cLBP.Compliance with ethical standardsEthical approval was sought from Umm-Al-Qura University (no. HAPO-02-K-012-2022-11-1221). An informed consent form was signed (or fingerprinted) by each participant before enrolment in our study and collecting any data.Statistical analysisData analysis was carried out using RStudio (R version 4.2.2). Frequencies and percentages were used to express categorical data. Tests of normality were applied to the scores of QOL, VAS, and ODI scales, indicating the non-normal distribution of the scores (p < 0.0001). Therefore, median and IQR were used to present continuous data. Additionally, we used non-parametric inferential tests to explore the statistical differences between different patient groups in terms of the QOL and disability scores. These included a Wilcoxon rank sum test for variables with two categories and a Kruskal-Wallis rank sum test for variables with more than two categories. The significantly associated variables from the inferential analysis were subsequently used in a multivariable generalized linear model to assess the predictors of disability using the disability score as a dependent variable. Results were expressed as beta coefficients and 95%CIs. A p-value of < 0.05 indicated statistical significance.Prevalence of cLBPThe prevalence of cLBP was calculated in this study; the numerator was the 238 patients with cLBP, and the denominator was the 918 adults who attended PHC settings seeking any medical service. Thus, 25.9% of patients were found to have chronic LBP  were indicated among 58.1% and 28.6%, respectively. Specific back pain, defined as pain associated with having an abnormal X-ray or MRI spine finding, was prevalent among 97.1% of patients under study , limited ROM of the spine p = 0.047), abnormal MRI findings (p = 0.033), and PVRV results (p = 0.003) , spine range of motion (p = 0.010), the outcomes of FST (p < 0.001), having abnormal X-ray (p = 0.025), having abnormal MRI lumbosacral spine (p < 0.001), PVRV (p < 0.001) and having specific back pain, defined as pain associated with having an abnormal X-ray or MRI spine finding  and higher VAS scores . Furthermore, disability was independently associated with having PVRV , as well as having abnormal X-ray findings ; in contrast, another study found that up to 90% of patients with cLBP may have no definite cause for this pain . This diAccording to previously reported results of the Oswestry survey, subjects with cLBP have a significantly higher disability score and lower QOL score ,21,24. TThe median QOL score in this study was 70 (60-80), which was higher than the results in a Cameron study, which revealed that the median QOL score was 50 (IQR: 25). This difference might be due to the elder study subjects in the previous study as the mean age was 52 years. We found that the median QOL was significantly related to age, limited movement, and abnormal radiologic findings. Similar associations were reported in another study, which showed that age, education, smoking, and abnormal imaging were associated with poor QOL .Upcoming disability, estimated by multiple linear regression analysis, was positively predicted by the VAS and abnormal X-ray findings and negatively predicted by the QOL score. Disability scores were independently predicted by lower QOL scores and higher VAS scores. Furthermore, disability was independently associated with having PVRV. These results could help in the early detection and avoidance of increasing pain and disability in patients with cLBP. Similarly, a fear of movement, pain severity, anxiety, and depression are consistently stated to predict disability. This highlights the importance of addressing these factors in the management of cLBP ,27.Limitations of the studyThe study was a cross-sectional analysis that could not explain a causal association, and a longitudinal study design will be needed to follow up on the cases and their progression to confirm the prediction of disability. In addition, it was conducted in primary care settings and in Makkah City only, so it could not be generalized to the general population.cLBP was common in adults attending primary care settings in Makkah City, with a higher frequency in women than men. It was associated with moderate disability and lower HRQOL. Disability scores were correlated negatively with the QOL scores and positively with the VAS scores. The findings highlight the significant impact of cLBP on disability, as well as HRQOL.


Chronic pain conditions create major financial and emotional burdens that can be devastating for individuals and society. One primary source of pain is arthritis, a common inflammatory disease of the joints that causes persistent pain in affected people. The main objective of pharmacological treatments for either rheumatoid arthritis (RA) or osteoarthritis (OA) is to reduce pain. Non-steroidal anti-inflammatory drugs, opioids, and opioid antagonists have each been considered in the management of chronic pain in arthritis patients. Naltrexone is an oral-activated opioid antagonist with biphasic dose-dependent pharmacodynamic effects. The molecule acts as a competitive inhibitor of opioid receptors at high doses. However, naltrexone at low doses has been shown to have hormetic effects and provides relief for chronic pain conditions such as fibromyalgia, multiple sclerosis (MS), and inflammatory bowel disorders. Current knowledge of naltrexone suggests that low-dose treatments may be effective in the treatment of pain perception in chronic inflammatory conditions observed in patients with either RA or OA. In this review, we evaluated the therapeutic benefits of low-dose naltrexone (LDN) on arthritis-related pain conditions. According to the International Association for the Study of Pain (IASP), pain is defined as “an unpleasant sensory and emotional experience associated with, or resembling that is associated with, actual or potential tissue damage”. Pain can be either temporary or acute, but it can also last for a long time. Persistent chronic pain conditions last longer than three months. Chronic pain is very prevalent in the United States . Based oThis narrative review of the literature examines a broad range of papers that discuss the potential therapeutic benefits of low-dose naltrexone in different biomedical contexts. We performed searches in PubMed using the search terms “Naltrexone”, “Low Dose Naltrexone”, and “chronic pain”, complemented with searches in Google Scholar to account for studies not covered in PubMed. Results were primarily filtered for date of publication (from 2012 to 2023). However, some earlier studies were also included to provide historical context for the current studies. References include the entire set of publications we retrieved, as well as other relevant sources pertinent to this literature review. The only language restriction was that we only selected papers written in English. Two authors conducted the initial search (P.D. and Z.F.), two authors examined whether these studies were appropriate for inclusion (A.J.v.W. and H.-J.I.), and all authors approved the final list of references. Our manuscript summarizes these peer-reviewed published studies, and we remain agnostic about the clinical efficacy of low-dose naltrexone.20H23NO4; MW: 341.4; trade names: Vivitrol, Revia) is a semi-synthetic opioid developed in the 1960s as an alternative to naloxone for opioid addiction treatment. It was first approved by the Food and Drug Administration (FDA) in 1984 for the treatment of opioid use disorder. Subsequently, the use of naltrexone was approved for alcohol dependency in 1994. The drug is prescribed in the range of 50 to 100 mg per daily dose and has been traditionally used to treat alcoholism or opioid use disorders [Naltrexone  where it works as an inhibitor at high doses and as an agonist at low doses  Figure . Consequpendence . It has pendence ,21,22. ANaltrexone is a bitter-tasting white crystalline compound that is soluble in water to a concentration of about 100 mg/mL. The solubility of the compound permits ingestion as an oral drug or delivery via injection of small volumes to reach daily doses (from 5 to 100 mg) for the treatment of substance dependency. For low doses, naltrexone is used in the range of 1 to 5 mg per day. At lower dosing, naltrexone may act beyond opioid receptor antagonism and modulate neuro-inflammatory processes, including attenuation of glial cells ,23. WhenThe plasma half-life of naltrexone varies depending on the route of administration. After oral administration of naltrexone, it takes 4 h to reduce the plasma concentration to half. The major active metabolite, 6β-naltrexol, persists in the biological fluid for a longer time (~13 h) and contributes to the pharmacological response of the drug ,25,26,27The fundamental reason for considering LDN in the treatment of chronic pain is that the biological effects of naltrexone do not conform to linear dosing or saturation curves. Rather, naltrexone has biphasic effects and follows hormetic principles, in which a full dose acts as an inhibitor but a low dose of a drug acts as a weak agonist ,26,27. TTheoretically, a complete blockade of endogenous opioid systems would not be a desirable outcome with chronic pain patients because it would inactivate a powerful physiological reward system that modulates our behavior and psychological perspectives. However, LDN may reduce pain and act agonistically by triggering positive feedback mechanisms. LDN causes a transient opioid receptor blockade that then prompts the body to compensate for reduced receptor activity by upregulating both endogenous opioids and opioid receptors ,29. For LDN may affect inflammation by modulating multiple immunological mechanisms. Apart from suppressing Substance P (TAC1), LDN has been shown to have anti-inflammatory effects on the central nervous system through glial cell regulation. LDN acts as a Toll-like receptor (TLR4) antagonist ,32. WhenConsistent with this concept, the TLR4 inhibitor TAK-242 (Resatorvid) has been examined in in vitro and in vivo animal models of RA, where Resatorvid improved inflammatory symptoms  . DespiteRheumatoid Arthritis and Seropositive Arthritis. LDN may have therapeutic potential in RA, which is an autoimmune condition characterized by chronic inflammation. Unlike OA, RA mainly affects the synovial lining of the joints rather than the articular cartilage [artilage . LDN mayartilage .One interesting study assessed if there is a beneficial relationship between LDN use and significant changes in the dispensing of medicines for rheumatoid and seropositive arthritis . This quOsteoarthritis. At present, there are no ideal disease-modifying drugs that treat both cartilage defects and pain in OA, which represents a disease involving the progressive breakdown of cartilage in articulating joints, most often affecting knees and hips. Initial therapy often includes anti-inflammatory drugs to reduce swelling and pain. LDN shows promise for the future in the treatment options for OA and has been considered in clinical trials . Ultra-low-dose naltrexone combined with traditional medications for the treatment of OA has shown better clinical outcomes than standard traditional medications [ications . Once thTo circumvent the major adverse effects of opiates, several novel treatment strategies have been developed. One very interesting pharmacotherapy utilizes Oxytrex, which represents a combination of oxycodone and ultra-low-dose naltrexone (ultra-LDN). In a three-week phase II clinical trial, Oxytrex was administered to OA patients with moderate to severe pain . In thisSubsequent studies on Oxytrex  revealedFibromyalgia. The immunomodulatory effects of LDN have been hypothesized to provide benefits for patients with fibromyalgia, which represents a neuroinflammatory condition characterized by widespread musculoskeletal pain associated with sleep, memory, and mood issues. There is some evidence indicating that LDN can provide pain relief and improve quality of life in patients [patients . In one patients ,41. Follpatients ,30. Studpatients . DespiteIn a more recent study, the dose–response relationship when treating fibromyalgia with LDN was explored . The stuMultiple Sclerosis. LDN is a possible treatment option for MS, a chronic and autoimmune disease of the central nervous system that manifests itself as either progressive or relapse-remitting MS [tting MS . Althougtting MS ,45.A limited number of studies have examined the therapeutic effects of LDN in patients with MS. In one retrospective chart review  after LDCrohn’s Disease. LDN has also been used as a novel treatment for Crohn’s disease, which is a multifaceted inflammatory condition affecting the digestive tract. Deregulated opioid signaling is often associated with Crohn’s disease, and this deregulation influences the secretion and motility of the gut. Recent studies have indicated the benefits of LDN for patients with Crohn’s disease , there are very few published studies at present. However, the currently available studies demonstrate both an improvement in symptoms and a decrease in serum markers. The future of treatment for MS using LDN is promising, but more studies are needed to demonstrate efficacy, safety, and replicability. For Crohn’s disease, LDN has proven to be safe while also improving the quality of life of patients. As with MS, larger clinical studies would help establish a clear protocol for the treatment of Crohn’s disease. LDN has been one of the most exciting novel treatment options for different types of arthritis. The limited number of published studies indicate that LDN decreases pain in patients and has few side effects. To further encourage LDN use in arthritis, more large-scale double-blinded studies are needed to examine the role of LDN. LDN shows promising use for future patients, but investments in clinical trials are required to investigate whether this treatment has significant benefits for patients with arthritis.