Pain severity, depression, and sleep disturbances are key targets for FM rehabilitation. Recent evidence suggests that whole-body cryostimulation (WBC) might be an effective add-on treatment in the management of FM. The purpose of this study was to evaluate the effects of an add-on WBC intervention to a multidisciplinary rehabilitation program on pain intensity, depressive symptoms, disease impact, sleep quality, and performance-based physical functioning in a sample of FM patients with obesity. We performed a randomized controlled trial with 43 patients with FM and obesity undergoing a multidisciplinary rehabilitation program with and without the addition of ten 2-min WBC sessions at −110 °C over two weeks. According to our results, the implementation of ten sessions of WBC over two weeks produced additional benefits. Indeed, both groups reported positive changes after the rehabilitation; however, the group that underwent WBC intervention had greater improvements in the severity of pain, depressive symptoms, disease impact, and quality of sleep. On the contrary, with respect to performance-based physical functioning, we found no significant between-group differences. Our findings suggest that WBC could be a promising add-on treatment to improve key aspects of FM, such as pain, depressive symptoms, disease impact and poor sleep quality. Fibromyalgia (FM) is a chronic and debilitating syndrome characterized by widespread pain, sleep disturbances, severe fatigue, depression, and cognitive impairment ,2. FM leFM, on the other hand, encompasses more than just pain, and depression and sleep disturbances should be prioritized for FM rehabilitation ,19. DeprFM patients report more sleep disturbances compared to the general population and individuals with rheumatic disorders ,27. The This vicious cycle is especially problematic in FM patients with comorbid obesity. Obesity affects approximately 40% of individuals with FM , and theGiven the wide range of symptoms and consequences of FM, the management of this condition requires a multidisciplinary approach that includes pharmacotherapy, physical therapy, and cognitive behavioral therapy . Non-phaWhole Body Cryostimulation (WBC) may be a useful treatment for addressing the nodes of this vicious cycle between pain, mood, and sleep ,41,42. WTo date, most studies have been focused on the effect of WBC on FM, reducing pain severity ,53, impaThus, this study aimed to determine whether the addition of WBC to a multidisciplinary rehabilitation program could result in a greater reduction in pain intensity, depressive symptoms, disease impact, and improvement in sleep quality and performance-based physical functioning in a sample of FM patients with obesity. We hypothesized that participants receiving an add-on WBC intervention would show greater improvements in (i) pain severity, (ii) disease impact, (iii) depressive symptomatology, (iv) sleep quality, and (v) performance-based physical functioning as compared to the controls.We conducted a randomized controlled trial on patients with FM and obesity who underwent a multidisciplinary rehabilitation program with or without the addition of WBC. Eligible participants were recruited consecutively from the in-patients of the Rehabilitation Unit of the IRCCS Istituto Auxologico Italiano . The hospitalization aimed at weight management and physical conditioning. The stages of the protocol are described in Data were collected from 1 June 2021 to 30 December 2021. Anthropometric values, body composition, demographic, and clinical data were collected at admission and at discharge within 4 weeks. Primary outcomes were assessed before the experiment (PRE-T0) and two weeks later (POST-T1) at the end of the study protocol. Subjects assigned to RWBC were familiarized with WBC at PRE-T0. Then, they underwent 10 sessions of WBC over a 2-week period . The multidisciplinary rehabilitation program consisted of a 3-h daily program including sessions of physiotherapy, nutritional and psychological support, and adapted physical activity classes .http://www.randomization.com website (accessed on 29 May 2021). Concealed allocations were performed by an independent researcher to prevent selection bias. This study was an open trial; thus, both participants and researchers knew which treatment the patient is receiving . Each participant received verbal and written information about the research protocol. All participants signed an informed consent form in which the study procedures were explained in accordance with the Declaration of Helsinki. The Ethics Committee of the Istituto Auxologico Italiano approved the study protocol and materials (code 2021_05_18_14).The following inclusion criteria were used: (i) age between 18 and 65 years; (ii) FM diagnosed by a rheumatologist according to the criteria of the American College of Rheumatology criteria; (iii) FM diagnosed for more than one year; meeting the Fibromyalgia research criteria measure with the Fibromyalgia Survey Questionnaire, Italian version . ParticiRehabilitation program. The multidisciplinary rehabilitation program consisted of individual nutritional intervention, psychological support, and supervised physical activity throughout hospitalization. All patients received a balanced hypocaloric diet consisting of 18–20% proteins, 27–30% fats (<8% saturated fat), 50–55% carbohydrates (<15% simple sugars), and 30 g of fibers from fresh vegetables. The diet plan was organized by the hospital dietitian into three meals  with an energy distribution of 20%, 40%, and 40%, respectively. Two daily 60-min physiotherapy sessions were performed under the supervision of a physiotherapist and consisted of: personalized progressive aerobic training, postural control exercises, and progressive strengthening exercises.WBC intervention. Patients assigned to the RWBC group were exposed to extremely cold, dry air at −110 °C for 2 min in a cryochamber  located at the Rehabilitation Unit of San Giuseppe Hospital, Istituto Auxologico Italiano, in Piancavallo, Italy. Patients minimally dressed, wearing a surgical mask, earband, gloves, t-shirt, shorts, socks, and plastic clogs, were first familiarized with the cryochamber  with a first 1-min session at −110 °C. Before entering the chamber, eventual glasses, contact lenses, and metallic jewelry were removed, and the body thoroughly dried. Regular vocal and eye contact with the patient was maintained during the session. The following sessions lasted 2 min at a temperature of −110°. The patient’s skin surface temperature was measured before and after each treatment with an infrared thermometer  at the neck, quadriceps, popliteal fossa, and calf level.2 where kg is a person’s weight in kilograms and m2 is their height in meters squared), and pain duration.Baseline demographic and clinical characteristics, collected at admission (PRE-T0) and discharge (POST-T1), included age, gender, body mass index  and after two weeks (T1).Pain severity. Perceived pain was assessed using a Pain Numeric Rating Scale (PNRS) ranging from 0 to 10, where high scores indicate high levels of pain intensity .Disease impact. The Fibromyalgia Impact Questionnaire (FIQ) , in its Depressive symptomatology. The Beck Depression Inventory (BDI-II)  is a selSleep quality. To assess perceived sleep quality, we used a Visual Analogue Scale from 0 to 10, where 0 corresponds to “worst possible sleep quality” and 10 “excellent sleep quality”.Performance-based physical functioning. The six-minute walk test (6MWT) was performed indoors, along a long, flat, undisturbed 30-m hospital corridor with the length marked every 5 m according to the “ATS Statement: Guidelines for the Six-Minute Walk Test”. Chest pain, severe dyspnea, physical exhaustion, muscle cramps, sudden gait instability, or other signs of severe distress were additional criteria for stopping the test. A higher score corresponds to greater walking endurance . In addiA sample size of 34 participants was deemed sufficient to detect a significant interaction between groups by time on outcomes, with an effect size of 0.25, a power of 80%, and an alpha level of 0.05.Summary statistics were used to describe the sample . Shapiro–Wilk tests, Q-Q plots, and histograms were used to evaluate the normality of the distribution of the PNRS, FIQ, BDI, VAS-Sleep, 6MTW, and TUG. Because the assumption of normality of the data was not respected, we decided to use a nonparametric approach. Baseline differences between the RWBC group and the R group in age, BMI, and pain duration were inspected using Mann–Whitney U tests. Then, a nonparametric ANOVA-type test was employed to assess the interaction between time and group on the dependent variables . The analyses of the time x group interactions were performed using the R (version 4.0.1) package nparLD . α-levelThe results of the nonparametric ANOVA-type test are presented in the following paragraphs. For each outcome, both the main effect of time and the interaction effect between group and time. The median and interquartile ranges (IQR) of the outcomes of the RWBC and R group at T0 and T1 are reported in p = 0.62. The main effect of time showed a statistically significant difference at the different time points in PNRS, Anova-Type Statistics (ATS) = 278.92, p < 0.0001, and also a statistically significant interaction between the group and time on PNRS, ATS = 56.42, p < 0.001, indicating that the RWBC group reported a significantly larger decrease in pain severity levels compared with the R group  and TUG  between group. There was no statistically significant interaction between the intervention and time on 6MWT, ATS = 0.11, p = 0.741. However, the main effect of time showed a statistically significant difference in median 6MWT at T1 compared to T0, ATS = 76.98, p < 0.0001  in patients with FM and obesity. We hypothesized that combining WBC with standard treatment would more effectively reduce pain severity, depressive symptomatology levels, and overall impact of the disease and improve sleep quality and performance-based physical functioning as compared to standard treatment alone. Our hypotheses were partially confirmed by the results. The implementation of ten WBC sessions over two weeks resulted in additional benefits. Indeed, both groups reported positive changes in all outcomes assessed after the rehabilitation period, but the magnitude of changes was statistically greater in the RWBC group, particularly for pain severity, depressive symptomatology, illness impact, and sleep quality. In performance-based physical functioning, however, we found no differences between the two interventions, with both groups improving at the end of the intervention but no differences between them. Nevertheless, our preliminary findings suggest that WBC may be a useful adjunct treatment for simultaneously improving several key aspects of FM and obesity.Our results are partially consistent with previous evidence. Rivera et al.  found a A recent prospective randomized, double-blind study found that 10 sessions of WBC significantly reduced depressive symptoms in adult patients who suffered a depressive episode . In contOne interesting aspect of our study is that sleep, mood, and pain have all improved, in line with previous evidence suggesting that these three factors interact and influence each other ,67,68,69Previous research has shown that WBC can improve muscle strength, cardiovascular and hormonal systems, lipid profile, and muscle recovery after exercise resulting in an overall improvement in functional status in athletes . HoweverThis study has some limitations, including the lack of biomarkers documenting WBC-induced effects, the open trial design, and the pre-post design with no follow-up. Since no sham treatment was provided, a placebo effect from our WBC intervention could not be ruled out. Additionally, several participants did not consent to undergo physical tests , resulting in missing data for those measures. Despite these limitations, WBC appears to have the potential to enhance rehabilitation programs and their cost-effectiveness in patients with FM and obesity. Because the coexistence of FM and obesity reduces functional capacities and increases self-perceived disability, additional rehabilitative resources are required. Identifying effective add-on interventions able to boost rehabilitation programs appears to be an important issue. Not secondarily, the patients’ high compliance with the sessions and satisfaction with the treatment reported in most studies seem to make WBC a preferred component of the rehabilitation program, which appears to be critical in the long-term management of FM and obesity.According to our findings, WBC is effective for reducing pain severity and improving sleep, and mood in patients with fibromyalgia and obesity. Importantly, pain reduction may facilitate compliance to physical activity intervention with a positive effect on both weight and pain management in patients with comorbid obesity. However, further studies with follow-up measures will be needed to assess the long-term beneficial effects and to explore the beneficial effect also on performance-based physical functioning.


Pain due to vascular needle insertion has been reported in 40–60% of hemodialysis (HD) patients. Evidence suggests that there is typically no single method for relieving the pain of inserting vascular needles in HD patients. This study aimed to compare the effectiveness of EMLA cream and Valsalva maneuver (VM) on pain severity during vascular needle insertion in HD patients.  This randomized, controlled, clinical trial was conducted on 90 patients undergoing hemodialysis in the hemodialysis unit of Kowsar Hospital, affiliated with Semnan University of Medical Sciences, in Semnan, Iran. Patients were selected via convenience sampling and were randomly assigned to one of the three groups . For the patients in the EMLA group, 2.5 g of EMLA cream was applied 60 minutes before the start of dialysis. For patients in the VM group, a maneuver was performed for 16–20 seconds before the needle was inserted. Patients in the control group received only routine care without any additional interventions. The pain severity in the three groups was measured using the visual analog scale (VAS) two minutes after vascular needle insertion. P < 0.001). Pairwise comparison of the mean pain severity showed that it differed significantly in the EMLA and VM groups from the control group (P < 0.001), but no significant difference was found between the EMLA and VM groups (P=0.067).  The results showed that the mean pain severity during cannulation was 2.06 ± 2.19 in the EMLA group, 3.2 ± 30.42 in the VM group, and 6.20 ± 1.49 in the control group, suggesting a significant difference between the groups  cannulation. Therefore, the use of EMLA cream and VM is recommended for reducing the severity of AVF cannulation pain.  Patients with end-stage renal disease (ESRD) need alternative kidney treatments such as hemodialysis (HD), peritoneal dialysis, or kidney transplantation to survive .Among these treatments, HD is the primary choice for patients ,3. SucceDialysis requires the use of at least one, and more commonly, two large gauge needles . Since tPain is an unpleasant feeling and an emotional experience that is associated with potential or actual tissue damage . The paiHarris et al. suggested that more than one-fifth of hemodialysis patients are unable to tolerate the pain caused by vascular needles  and 47% The prevalence of pain due to vascular needle insertion in HD patients has been reported with similar rates in almost all studies. For instance, Alzaatreh et al. in Jordan reported this prevalence as 57%, Kortobi et al. in Morocco as 40–60%, and Da-Silva et al. in Brazil as 58.5% –18.Pain control during vascular needle insertion in HD patients can be important for two reasons: First, pain adversely affects the patients' quality of life ; second,Among health care personnel, nurses play a key role in reducing patient's pain. Nurses typically use two approaches to reduce the pain of AVF insertion in HD patients: Pharmaceutical and nonpharmaceutical approaches . The effIn Iran, there is usually no single method to relieve AVF cannulation pain in HD patients . Pain reP < 0.001) [EMLA cream is a topical anesthetic combination of the two topical anesthetics lidocaine 2.5% and prilocaine 2.5% . By chan< 0.001) . The use< 0.001) .Kortobi et al. also studied the effect of cryotherapy in comparison with EMLA cream in the management of AVF puncture pain. The results showed that the analgesic effects of both techniques were approved, but cryotherapy provided higher efficiency and fewer restrictions for patients and could be suggested for AVF puncture pain management .P < 0.001). PerformingVM for 16–20 seconds during needle insertion into a vein can reduce the incidence and severity of pain experienced by the patient [The Valsalva Maneuver (VM) is also a noninvasive method for controlling AVF puncture pain . This meAlthough many studies have shown the effectiveness of EMLA cream ,32,33 ann=((z1-α/2 + z1-β)2×(δ12 + δ22))/(μ1-μ2)2), the sample size was taken as 30 per group. The effect size was estimated as1.04 in G∗power software. A total of 100 people were recruited for the study. Ten of them were excluded for various reasons and the analysis was finally performed on 90 patients (30 subjects per group). The eligible patients were randomly assigned to one of either control, VM, or EMLA cream groups  and was registered in the Iranian Registry of Clinical Trials (IRCT20120109008665N12). The researchers started collecting the data after obtaining permission from the officials of Kowsar Hospital and the hemodialysis unit. In a meeting before the intervention , the researchers visited the hemodialysis unit, introduced themselves to the patients, and gave sufficient explanations about the research objectives and work method, confidentiality of the data, and the voluntary nature of participation in the study. The patients' questions were also answered and written consent was obtained from them to participate in the study.In the introduction session, the patients in the EMLA cream group were given a 5-gram EMLA cream of 5%  and a transparent dressing and were instructed to apply half of the cream to the area on their skin where the needle would be inserted and cover it with a transparent dressing without rubbing the area, one hour before the start of their next dialysis session, at home. The patients in the VM group were instructed on how to blow into a disposable plastic tube connected to a mercury barometer  to the point that the mercury column would raise to 20–25 mmHg for 16–20 seconds. No special intervention was performed on the control group and they received only routine care measures.In the next dialysis session, in the EMLA group, after removing the transparent dressing and cleaning the skin, the area was disinfected with 70% alcohol-soaked cotton. AVF cannulation was performed and fixed by the patient's dedicated nurse and the patient's pain was measured using the visual analog scale (VAS) two minutes after arterial needle insertion.In the VM group, the patients were asked to blow in a plastic tube connected to a mercury barometer after taking a deep breath, so that the mercury column would raise to 20–25 mmHg for 16–20 seconds. After performing VM and after disinfection of the area with 70% alcohol-soaked cotton, AVF cannulation was performed and fixed by the patient's dedicated nurse and their pain was measured using VAS two minutes after arterial needle insertion.In the control group, after disinfecting the area with 70% alcohol-soaked cotton, AVF cannulation was performed and fixed by the patient's dedicated nurse and their pain was measured using VAS two minutes after arterial needle insertion.To ensure the homogeneity of the procedure in all three groups, a skilled hemodialysis nurse inserted a hemodialysis needle No. 16  into the veins from a distance of at least 5 cm from the fistula at a 30–45° angle with the bevel of the needle facing up.It should be noted that since local anesthesia occurs 60 minutes after applying EMLA cream depending on the site, cannulation was performed 60 minutes after using EMLA cream .The data collection tools in this study were a demographic information questionnaire and VAS. The demographic information questionnaire included items such as age, sex, marital status, education, the underlying cause of CRF, time since the start of dialysis, duration of dialysis sessions, and frequency of dialysis per week.The patients' pain severity was assessed using VAS on a scale of 0 to 10. The patients were asked to choose a number from 0 (no pain) to 10 (the most severe pain imaginable) for the severity of pain experienced after the needle was inserted. On this scale, pain severity is divided into four groups: painless (0), mild pain (1–3), moderate pain (4–7), and severe pain (8–10) . AlghadiU test was administered for the pairwise comparison of the mean pain severity during vascular needle insertion in the three groups.Data analysis was performed using the perprotocol approach in SPSS-19 statistical software  at a significance level of 0.05. By drafting the absolute and relative frequency tables, the research data were described, categorized, and compared. To analyze the data, first, the Kolmogorov‒Smirnov test was used to determine the normal distribution of data. The Chi-square test was then used to compare the absolute and relative frequency of the subjects in terms of gender, the underlying cause of CRF, duration of each dialysis session, and frequency of dialysis per week. The ANOVA was used to compare the absolute and relative frequency of the subjects in terms of age and duration of dialysis. The Kruskal–Wallis test was used to compare the mean pain severity experienced by the subjects during AVF cannulation, and the Mann‒Whitney post-hoc P > 0.05).The present study was conducted on 90 patients undergoing hemodialysis. The mean age of the patients was 54.11 ± 13.49 years. Most patients in the EMLA cream and VM groups (76.7%) and 63.3% of the patients in the control group were males. P < 0.001)  and VM (46.7%) groups but moderate (60%) and severe (40%) in the control group. In terms of pain severity during AVF cannulation, the lowest mean pain severity pertained to the EMLA cream group (2.06 ± 2.19) and the highest mean pain severity to the control group (6.20 ± 1.49). The mean pain severity in the VM group was 3.2 ± 30.42. The Kruskal‒Wallis test showed a significant difference in pain severity during AVF cannulation between the three groups (< 0.001) .U test) for the pairwise comparison of the mean pain severity of the groups showed that the pain severity differed significantly between the EMLA vs. control (P < 0.001) and VM vs. control group (P < 0.001), but no significant difference was found between the EMLA and VM groups themselves (P=0.067)  .The results of the present study, which was conducted to compare the effect of EMLA cream and VM on pain severity during AVF cannulation in HD patients showed that EMLA cream and VM provide similar pain relief. To the best of the researchers' knowledge, no clinical trials have compared the pain-relieving effects of EMLA cream and VM on AVF cannulation to date.Compared to the controls, the mean pain severity after cannulation was significantly lower in the EMLA group, followed by the VM group. The results showed a significant difference in pain severity between the three groups. The pairwise comparison of the mean pain severity also showed a significant difference in pain severity between the EMLA cream and control groups and between the VM and control groups. No significant difference was found between the EMLA and VM groups.P=0.00001) compared to the lidocaine tape [In line with this finding, several other studies have been conducted to investigate the effect of EMLA cream or VM in reducing pain caused by venipuncture and AVF cannulation, confirming the effectiveness of these methods ,33,49–51ine tape . The resine tape . The resine tape . The reaSeveral studies on VM have also confirmed the effectiveness of this nonpharmacological method in reducing pain severity. The results of a study by Vijay et al. to investigate the effect of VM on the severity of peripheral venous cannulation pain showed that the mean score of subjective pain was significantly lower in the VM group compared to the control group . In someThe relief of the pain due to AVF cannulation in hemodialysis patients can be caused by the activation of the cardiopulmonary baroreceptor reflex arc or the Sino aortic baroreceptor arc following VM. Activation of the baroreceptor can stimulate the vagus nerve. The activated vagus nerve then sends impulses to the nucleus of the solitarius tract. The solitarius tract is the point of intersection between the afferent nerves of the nervous system and the nociceptive pain pathways in the spinal lamina . Pain reRegarding the mean pain severity, the results did not show a statistically significant difference between the EMLA (2.06) and VM (3.30) groups. This difference was, however, clinically significant. Only one study compared the severity of pain after venipuncture following the use of EMLA cream and VM, which yielded consistent results with this study .In the present study, side effects such as localized pallor were observed in ten patients following the use of EMLA cream, while side effects such as bradycardia, hypotension, or fainting were not observed during or after VM.According to the researchers, before proposing EMLA or VM as a preferred method to reduce the severity of pain in patients during AVF cannulation, the following points should be considered. The use of EMLA cream is not only limited by specific considerations, mainly related to its duration of action (30–60 minutes) and contraindications , but will likely cause some side effects as well . EMLA cream is also not readily available in many countries, including Iran, and is not economically viable for most patients  . In contThis study confirmed the hypothesis that EMLA cream is clinically superior to VM, although no statistically significant difference was observed between the two approaches.One of the most important limitations of the present study was the decrease in the internal validity of the study due to its lack of blinding. Pain is a subjective phenomenon that is reported by the individual and every person has a different opinion about the severity of pain they experience, which can lead to the over or underestimation of pain. Further studies with larger sample sizes and the use of objective criteria for assessing pain severity, blood pressure, and heart rate monitoring before and after cannulation, and measuring the serum levels of lidocaine and prilocaine to determine the safety of EMLA cream up to 90 minutes after use are some of the measures recommended obtaining more precise evidence on the effectiveness of VM and EMLA cream in reducing the severity of AVF cannulation pain.Based on the results, VM is as effective as EMLA in reducing the pain caused by AVF cannulation. Due to the importance of the management of pain as the fifth vital sign, and the side effects of its poor control, the use of VM and EMLA cream is recommended for reducing the severity of pain caused by AVF cannulation in HD patients. Due to the lack of easy access to EMLA cream and the problems with pharmaceutical methods, using VM as an independent complementary/alternative nursing measure is recommended.


To study reduction in pain score after treatment with intravenous regional anesthesia (IVRA) and Stellate ganglion block (SGB) combination on complex regional pain syndrome (CPRS) patients and to quantify patients’ satisfaction with treatment and occurrence of complications.This is a record-based retrospective review carried out in 2020, targeting patients treated in the University of Jordan Hospital, Amman, Jordan, over the years 2002-2020.Among 99 patients, a significant drop in pain scores occurred in 88% of the patients’ sample. Gender, age, type of CRPS, and duration of symptoms didn’t affect statistical results. An average of 8.6 sessions needed to achieve 50% drop in pain score, and 2-3 sessions for first clinical improvement. Patients with previous application of plaster of Paris had increased success rates.We find it practical, inexpensive, safe, and straightforward to combine SGB with IVRA for CRPS patients. Since its description in the literature (around 1870) complex regional pain syndrome (CRPS) has proven to be one of the most difficult pain disorders to treat, and it continues to cause major limitations to the daily activities of its victims. Diagnosis of CRPS is basically clinical using the the International Association for the Study of Pain (IASP) and Budapest criteria. Two types of CRPS exist . Complex regional pain syndrome is more prevalent among females.Complex regional pain syndrome is one of the most debilitating pain syndromes causing major psychological consequences, most commonly depression, and approximately 30% of patients have considered suicide during their illness.Sympathetic dysfunction is a major factor in CRPS pathogenesis, and various approaches to sympathetic blockade have been used for treatment. The mechanism of SGB may involve central mechanisms altering nerve growth factors, resulting in relief of symptoms for durations longer than expected from local anesthetic action alone.Lidocaine has been used in intravenous regional anesthesia (IVRA) and Stellate ganglion block (SGB) as an adjunct during surgical repair, with physiotherapy sessions to improve success in treating CRPS. A survey was carried out on the prevalence of CRPS in the Jordanian population and studied the effectiveness of previous treatments. In our search in the literature, unlike peri-operative use of IVRA, we found no previous use of steroids in intravenous regional blocks for CRPS.The available evidence on CRPS in the Middle East and North Africa is limited.A practical, easy, and inexpensive method of treating CRPS is greatly needed. In this study, we present our experience with carrying out a combination of a SGB and IVRA for the treatment of CRPS patients in settings with limited resources, and evaluate the effectiveness of that combination in reducing pain scores in our patients.The objectives of this study included; I) studying reduction in pain score after treatment with IVRA, SGB combination on CPRS patients, and to quantify patient satisfaction with treatment and occurrence of complications; II) studying the effect of age, gender, total number of blocks, plaster of Paris application, and duration of symptoms on treatment success and number of therapeutic sessions needed to achieve success; and III) comparing outcomes of the combination for upper and lower limbs.This is a record-based retrospective observational study carried out in 2020 at the University of Jordan Hospital, Amman, Jordan.We referred to pain clinic data to search for CRPS patients’ data, over the years 2002-2020, and collected 103 records of patients diagnosed with CRPS, after which we applied inclusion and exclusion criteria to obtain 99 eligible records.Inclusion criteria included: I) all cases of CRPS patients who were referred for invasive chronic pain management from 2002-2020; II) who had not responded to oral analgesics and physiotherapy in 4-8 weeks; and III) had pain scores of >8 of 10 at the beginning of treatment sessions.Exclusion criteria included: I) cases of patients with more than one extremity involved simultaneously; II) those who did not undergo combined IVRA and SGB treatment; and III) those whose medical records did not contain complete data .The diagnosis of CRPS was based on the IASP criteria before 2007, then on the Budapest criteria after 2007.In each therapeutic course, all patients received a combination of IVRA and SGB ipsilaterally in the same session. All patients were monitored with the standby IV access on the unaffected limb. Intravenous regional anesthesia was lidocaine 0.5-20% mL  for children, and 40 mL for adults (through a 22G cannula after exsanguination of the limb and inflation of the pneumatic tourniquet to 100 mmHg above systolic pressure for 30 minutes). Simultaneously, a SGB was carried out with 5 mL of plain lidocaine 1% on the ipsilateral side. Follow up sessions were carried out weekly.Data collected included: patients’ age, gender, medical history, type of symptoms, type of CRPS, precipitating factor, duration of symptoms, type of regional anesthesia treatment, total number of courses of regional blocks and the course at which first improvement was encountered, occurrence of complications from treatment, referral to physiotherapy, and history of plaster of Paris application. Satisfaction with treatment was measured with a 10-point Likert scale ranging from 1-10 (1=meaning least satisfied and 10=meaning most).We defined a patient’s first improvement as the first course at which the VAS score had dropped to 7 of 10 or less. Success of treatment was defined as a pain score dropping to less than 5 of 10 (a 50% reduction in pain score).This work obtained an approval from the Institutional Review Board (IRB) of Jordan University Hospital, Amman, Jordan, before data collection (Grant No. 10/2020/15019). Due to the retrospective nature of this study, our institutional IRB waived the requirement to obtain written informed consent before starting data collection. We adhered to the tenets of the Declaration of Helsinki and Good Clinical Practice guidelines.p<0.050.Microsoft Excel 2007 software was used for data entry and data were then migrated to the Statistical Package for the Social Sciences software, version 25.0 . We analyzed data of 99 eligible cases; final sample’s data, features, and characteristics were summarized using mean ± standard deviation (SD) for normally distributed continuous variables and comparison was carried out by the student T-test, the median for non-normally distributed continuous variables. Comparison of means was carried out using Mann-Whitney test and Chi-square analysis for percentages. Significance level was established as Our patients were in the young age group, with an average of 38.3 years (range: 11-68). Other data is summarized in Although CRPS is basically a clinical diagnosis, patients were sent for limb X-ray and 3-phase bone scans. Some patients needed electromyography and nerve conduction studies to diagnose nerve injury. Only 12% of the patients had typical 3-phase positivity and 63% had osteopenia on the X-ray. A nerve conduction study was used to diagnose nerve injury (type II CRPS).Success rate for the whole sample was 87% (defined as a target drop in pain score >50% of baseline). These patients needed an average of 8.59 therapeutic sessions to achieve target. The average number of therapeutic courses needed to reach the first improvement (drop in pain score to less than 7 of 10) was 2.63 sessions.Males accounted for 65% of the sample, of which 56 (87.5%) had successful treatment, with an average satisfaction score of 5.4 of 10, an average of 7.6 therapeutic courses needed to achieve success, and an average of 2.2 courses to achieve first clinical improvement.Of the 35 female patients, 88.5% had successful therapy and needed 10 therapeutic courses on average to achieve success, an average of 3.4 therapeutic courses needed to achieve first clinical improvement, and a satisfaction score of 6.1 of 10.p=0.56).A Mann-Whitney-U test was carried out to study the gender effect on pain scores before and after treatment; it showed no statistically significant difference  as follows: 45 cases of bone fracture, 34 cases of tendon/soft tissue cutting trauma, and 8 patients with blunt trauma. Six patients developed CRPS after elective surgery for non-trauma causes, one patient after a burn, and 5 cases with no clear cause.p=0.47). The T-test showed no statistically significant difference between the 2 types of CRPS on patient satisfaction (p=0.66) and the number of therapeutic courses needed for successful treatment (p=0.56). Studying site of affected limb showed that most sample patients (83.8%) had upper limb involvement, with a successful treatment rate of 86.7%, an average of 8.7 therapeutic courses needed to achieve success, an average of 2.4 courses needed to achieve first improvement, and a score of 5.1 of 10 for patient satisfaction with treatment.Effect of type of CRPS on the study outcome showed that most patients had type I CRPS (79.8%). Patients with both types of CRPS had an approximate percentage of successful treatment. A Mann-Whitney-U test was carried out to study the effect of the 2 types of CRPS on pain scores before and after treatment; it showed no statistically significant difference .A Mann-Whitney-U test was carried out to study the effect of affected limb location on pain scores before and after treatment; it showed no statistically significant difference (p=0.35). There was no statistical correlation between the duration of POP and the number of sessions needed for successful treatment (Spearman’s rho= -0.11).A total of 68 patients had plaster of Paris cast applied to the affected limb as part of trauma management and 97% of them had successful treatment. A Mann-Whitney-U test did not show a statistically significant effect of Paris plaster application on pain scores before and after treatment (Only 5 cases had minor hemodynamic changes (3 cases of bradycardia and 2 of hypotension). They were short term, improved with fluid management, and did not lead to serious complications. The most common complication was increased weakness of the affected limb during the procedure (56%), which resolved within one hour after the procedure. This was followed by cuff discomfort (17%), which was resolved in a few minutes after cuff deflation. Only 2 patients had Horner’s syndrome in one of the therapeutic courses with no concomitant hemodynamic changes, and it was completely resolved in a few hours soon after. Other minor complications, such as tinnitus or dizziness, had an incidence of 3%.Patients with affected lower limbs had lower rates of complications (31%) than patients with upper limb involvement (57%).In regard to risk factors, our sample had little incidence of chronic illnesses other than .As expected from all chronic pain conditions, most CRPS patients face psychological problems, and psychiatrists play an important role in multimodal approaches to treatment, but unfortunately, few of our patients agreed to be referred to a psychiatrist, mostly due to fear of social stigma.Access to chronic pain services in Jordan and the Middle East is limited. This study summarizes our experience (2002-2020) treating patients with CRPS, for whom first lines of therapy had failed, using a combination of IVRA and SGB.Although the results of our study showed that 88% of our sample had successful treatment (a decrease of >50% in pain score from the baseline). Patients needed 2-3 sessions for first clinical improvement, and 8-10 sessions for pain score to drop below 50% from baseline. This may be explained by the population in the Middle Eastern region being younger in general, the scarcity of facilities for diagnosing CRPS, limited knowledge of doctors and patients regarding chronic pain conditions, and because in most cases of trauma, patients may have easier access to a chronic pain physician as part of referrals for their continuous care.Contrary to the European literature, in which most CRPS patients are elderly and female, our sample patients were young workers and mainly male.The application of Paris plaster cannot be controlled by the chronic pain physician; it is carried out by the primary physician managing the trauma near the time of the incident (before the development of chronic pain). Although its application is known to increase the risk of developing CRPS, in our sample, those with a history of Paris plaster application had a higher rate of successful treatment using the IVRA and SGB combination therapy.Similar outcomes of a therapeutic SGB in the upper and lower limb groups point to the central mechanism, leading to improved outcomes in the lower limb group as well as in the upper limb group.The combination of IVRA and SGB appears to be safe, as most complications were minor and self-limiting, and did not hinder the use of this technique for the treatment of CRPS cases. Approximately 14% of the sample patients presented to us with symptoms persisting for more than one year . Although we did not find a statistically significant effect of the duration of symptoms on short-term outcomes in our sample data , we believe that earlier treatment enhances better outcomes and earlier return to function.In general, Jordanians, like other Middle Eastern healthcare providers, have limited knowledge of chronic pain conditions and limited facilities to diagnose and treat CRPS in particular, which led to limited access of patients to chronic pain physicians, misdiagnosis of CRPS by non-specialized healthcare providers, and delayed presentation of many patients to specialized pain services.In contrast to previous research, we found similar results for types I and II CRPS in response to therapeutic sessions in our sample, which may be related to a misdiagnosis of nerve injury or to an occurrence of statistical type B error due to the small number of type II patients.Regarding cost, it was difficult to obtain actual prices of materials and equipment, but in a rough estimate of our technique, there was no expensive equipment or medications, no need for hospital admissions (it is an outpatient procedure), and patients with low to average income could afford our treatment sessions.I) Absence of a control group and non-blinding of data due to the retrospective nature of this study; II) lack of long-term patient follow-up because most patients were referred from other medical centers in distant areas; and III) the small sample size.Implications for further research includes: a multi-centric randomized controlled trial involving IVRA and SGB for CRPS patients and use of pharmacological additives to this technique.In conclusion, we found that the combination of IVRA with SGB for the treatment of CRPS patients is practical, inexpensive, safe, and straightforward, with a high success rate for both upper and lower extremity involvement, in both types of CRPS, and equally in both genders and among different age groups.


Evidence shows that chronic prostatitis/chronic pelvic pain syndrome hugely impacts the body and mind. The central mechanisms in patients with CP/CPPS resulted in increased attention as neuroimaging techniques developed. This review investigated the study design and major neuroimaging findings in CP/CPPS patients to provide comprehensive evidence. Seven databases were searched and screened: PubMed, EMBASE/SCOPUS, Cochrane Library Database, China National Knowledge Infrastructure, VIP, Wanfang, and China Biology Medicine disc. Nine studies were eventually included in the analysis. The results demonstrate that the insula, anterior cingulate gyrus, postcentral gyrus, and precuneus are significantly associated with CP/CPPS patients' pain feelings and cause dysregulation of painful emotions, lowering patients' tolerance to stimulus. Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common urological disorder characterized by pelvic pain or discomfort and abnormal urination . EpidemiThe advancement of neuroimaging techniques has aided in identifying functional/structural brain alterations in patients with chronic pain disorders, including CP/CPPS and chronic low back pain . The CP/Inclusion criteria are as follows: (1) controlled trial; (2) patients with CP/CPPS (type III); (3) pain in the perineum and pelvic area; (4) disease course of at least two weeks; (5) outcome measures including pain in the perineum and pelvic area and fMRI/MRI data.Exclusion criteria are as follows: (1) Animal experiments, case reports, pharmacological-pharmacokinetic studies, or literature reviews; (2) study subjects had urological disorders other than CP/CPPS, including erectile dysfunction, infertility, and other male diseases; (3) history of using alcohol or any drug that influences the brain function or structure such as psychotropic drugs.Computer searches of seven databases  were conducted for articles published since the database's inception until September 1, 2021, for CP/CPPS neuroimaging studies based on MRI/fMRI technology.The search was performed using a combination of subject headings and free words. The English search terms include the following: (“prostatitis” [MeSH Terms] OR “prostatitis” [All Fields] OR (“chronic” [All Fields] AND “prostatitis” [All Fields] AND “chronic”[All Fields] AND “pelvic” [All Fields] AND “pain” [All Fields] AND “syndrome” [All Fields]) OR “chronic prostatitis chronic pelvic pain syndrome” [All Fields] OR) AND (“magnetic resonance imaging” [MeSH Terms] OR (“magnetic” [All Fields] AND “resonance” [All Fields] AND “imaging” [All Fields]) OR “magnetic resonance imaging” [All Fields] OR “MRI” [All Fields]) AND (“brain” [MeSH Terms] OR “brain” [All Fields]). Supplementary Materials include the corresponding search terms used in the Chinese search. Chinese search terms are listed in Supplementary Two fully independent evaluators screened the literature based on the inclusion and exclusion criteria, respectively. First, duplicates and those who did not meet the inclusion criteria were eliminated by reading the title and abstract; second, the full text was read again, and the results were cross-checked for potential inclusion. Any disagreement was solved by the two evaluators through discussion and negotiation, and if no agreement was reached, a third evaluator was asked to review the literature further. If the authors have not provided the activation zone coordinates in the text, the evaluator should send emails to the authors to ask about data; if the authors do not respond within two weeks, the study will be excluded from the ALE analysis.The following data were extracted from the literature based on the inclusion criteria: (1) general information: title, author, journal, country or region of origin, and publication date; (2) study characteristics: study subject sample size, age, handedness, education, duration of illness, type of trial, CP/CPPS diagnostic criteria, baseline and intervention criteria, imaging methods, clinical/behavioral indicators, and emotional indicators; (3) nodal indicators: abnormal brain areas and trends in CP/CPPS, coordinates, and clinical correlation. The current systematic review was performed following the PRISMA checklist. The likelihood estimation (ALE) is a coordinate-based functional analysis approach proposed by Turkehaub et al.  to localp-FWE <0.05, voxel thresholds were p-uncorrected < 0.05, and the number of thresholding permutations was 5000. Brain region image results were presented using the DPABI toolbox (https://rfmri.org/).Specifically, (1) the Talairach coordinates were converted to MNI  coordinates using the coordinate conversion function of the Icbm2tal software. The coordinates were grouped and entered into the Ginger-ALE software according to the data entry method in the ALE manual. (2) Data were analyzed, and ALE maps were calculated using Ginger-ALE 2.3 software. Based on the peak maximum activation coordinates, a three-dimensional Gaussian distribution was modeled with the following parameters: the Gaussian filtered full width half maximum (FWHM) value was used as the default setting based on the number of subjects, and the software calculated the whole-brain ALE distribution. Cluster thresholds were A total of 247 English and 39 Chinese records were obtained through preliminary retrieval. After checking titles and abstracts, 277 duplicates and those that did not meet the inclusion criteria were eliminated; 0 were excluded by further reading the full text. Finally, nine studies were included (S1–S9); those published between 2011 and 2021 were included in this review ; Table 2The nine studies enrolled 431 study subjects, including 233 patients with CP/CPPS and 198 healthy subjects (HC). Eight of the nine studies  compared CP/CPPS patients with HC, while 1 study (S5) recruited only CP/CPPS patients. The maximum sample size for a single group of patients with CP/CPPS 31 was 19 in nine studies.One of the nine studies (S5) used acoustic magnetic therapy in the treatment group and sham stimulation in the control group. The other eight studies used healthy subjects as control groups.All studies required patients to be right-handed; two studies  required subjects to empty their bladders before the MRI examination; two studies  required subjects to have a visual analog score of 0 before the MRI examination; six studies  required subjects to be resting with their eyes closed but not asleep; three of these studies  did not specify any patient requirements.All studies adopted magnetic resonance imaging (MRI) to detect changes in the structural/functional activity of the brain of CP/CPPS patients. Five of the nine studies examined structural changes. Two studies  used diffusion tensor imaging (DTI) techniques to compare the global functional connectivity of brain white matter structures in CP/CPPS patients and healthy subjects. Two studies  compared regional gray matter  and white matter  features and functional brain connectivity in patients with CP/CPPS to those in healthy subjects using DTI and high-resolution T1-weighted MRI. Another study (S3) compared the functional connectivity of motor cortex areas directly controlling the pelvic floor in patients with CP/CPPS and healthy subjects using T1- and T2-weighted MRI image analysis. Two studies  used rs-fMRI to assess the mean regional homogeneity (ReHo) values of voxels in standardized brain regions. One study (S5) investigated the possibility of longitudinal cerebral blood flow (CBF) changes in CP/CPPS patients using arterial spin labeling (ASL) techniques. Another study (S2) investigated the role of the anterior cingulate cortex in chronic pelvic pain syndrome using T1-weighted MRI.The findings of nine studies revealed that patients with CP/CPPS had changes in 39 brain regions, primarily the left anterior cingulate cortex, right anterior cingulate cortex, right insula, left postcentral gyrus, left precentral gyrus, and left precuneus.Four studies  discovered changes in the anterior cingulate cortex (ACC) in CP/CPPS patients versus healthy subjects. Two of these studies  revealed changes in the ACC function, with a significant decrease in the ReHo value of the bilateral ACC and a significant negative correlation between the degree of activation of the bilateral ACC and the National Institutes of Health-chronic prostatitis symptom index (NIH-CPSI) scale pain score. Another study (S2) demonstrated changes in ACC structure, including a significant decrease in volume and an increase in density in the gray matter of the left ACC brain. Another study (S5) revealed that CBF was downregulated in the anterior cingulate cortex of patients.Three studies  found insula (INS) changes in CP/CPPS patients versus healthy subjects. One study (S4) revealed structural changes in the INS and a significant reduction in ReHo in the insula cortex of CP/CPPS patients. Two studies  correlated the functional changes in INS, functional activation within the patient's right anterior insula, and pelvic-motor connectivity to the right posterior insula with pain intensity in CP/CPPS.Three studies  found changes in the structure of the postcentral gyrus (PoCG), precentral gyrus (PreCG), and precuneus (PCUN) in CP/CPPS patients, all with significant increases in the values of the local efficiency attributes. The overall efficiency value of the left PoCG increased. The NIH-CPSI scale total score, the pain and discomfort symptom score, and the impact of symptoms on quality of life score all had a positive correlation with the local efficiency of the left PCUN.Two studies  found increased CBF in the left dorsomedial and right dorsolateral prefrontal cortex resulting in functional changes in the dorsolateral prefrontal cortex (DLPFC).Two studies  revealed changes in thalamus (THA) function, including significantly higher ReHo values and homogeneity in the right thalamic area and a significant positive correlation between the degree of activation in the right thalamic area and the NIH-CPSI scale pain score.Two studies  found changes in medial prefrontal cortex (mPFC) function and increased CBF in patients' left medial and right dorsolateral prefrontal cortex.Two studies  revealed structural changes in the middle frontal gyrus, orbital (ORBmid), median, and paracingulate gyrus (DCG), supplementary motor area (SMA), right superior temporal gyrus (STG), left superior marginal gyrus (SMG), left superior parietal gyrus (SPG), left posterior cingulate gyrus (PCG), and paracentral lobule (PCL) in CP/CPPS patients. The right middle frontal gyrus (orbit) is inefficient in CP/CPPS patients, implying a disruption in the connection of the entire brain to the right middle frontal gyrus (orbit). Local efficiency attribute values increase significantly in the left paracingulate gyri, supplementary motor area, right superior temporal gyrus, left supramarginal gyrus, left superior parietal gyrus, and left posterior cingulate gyrus. The overall efficiency of the left paracingulate gyrus and left posterior cingulate gyrus is improved. The NIH-CPSI scale total score, pain and discomfort symptom scores, and symptom impact on quality of life scores were all positively correlated with the right supplementary motor area .A total of 207 subjects were included in the ALE analysis, consisting of 9 studies, 29 foci, and a total of 2 significant clusters. Cluster 1 included the insula and superior temporal gyrus, and cluster 2 consisted mainly of the cingulate gyrus region .A narrative review of nine studies on brain MRI in CP/CPPS patients revealed a close association of clinical pelvic pain symptoms with functional or structural changes in brain regions, including left ACC, right ACC, right INS, right STG, and left PCUN in male CP/CPPS patients.This systematic review found structural changes in the ACC in CP/CPPS patients in four studies . The ACC is a critical brain region component of the neural substrate involved in pain processing . Lin et Three studies  found structural changes in the INS of CP/CPPS patients. Two studies  found functional activation of the right anterior insula in CP/CPPS patients. Mounting evidence from pain studies shows that the insula capitol cortex, which plays a critical role in chronic pain, is the brain region most consistently activated –17. The Three studies  found structural changes in PCUN in CP/CPPS patients. Positive correlations were found between the local efficiency of the left PCUN and the NIH-CPSI scale total score, pain and discomfort symptom score, and symptom impact on quality of life score. These findings demonstrate that the higher the local efficiency of the left PCUN, the more severe the patient's pain symptoms. The PCUN is the functional core of the posterior DMN , and it The ALE result suggests significant INS, STG, and ACC changes in patients with CP/CPPS. In S9, the ratio of STG network efficiency is more significant in patients than in healthy individuals. Robust evidence  suggestsChronic pelvic pain syndrome is a centralized pain syndrome associated with central nervous system changes. Abnormal regulation and output of the hypothalamic-pituitary-adrenal (HPA) axis are frequently related to centralized pain disorders. The HPA axis is the primary stress response system, and its activation induces cortisol production and immune response dampening. Patients with centralized pain syndromes frequently have hypercortisolism or hypocortisolism, and evidence of altered downstream signaling from the HPA axis, including increased mast cell (MC) infiltration and activation, can cause sensitization of nearby nociceptive afferents. Increased peripheral input via nociceptor activation can result in “hyperalgesic priming” and “wind-up,” which may eventually cause central sensitization via long-term potentiation in the central nervous system . CP/CPPSStudies reviewed herein revealed that critical regions played a role in pain relief. Opioid signaling in the anterior cingulate cortex, activation of midbrain dopamine neurons, and dopamine release in the nucleus accumbens are all required for the rewarding effect of pain relief . The venThe changes in brain regions of CP/CPPS patients are primarily concentrated in the left ACC, right ACC, right INS, right STG, and left PCUN. The ACC receives pain signals via the thalamus, amygdala, and insula cortex, and the regional homogeneity of bilateral ACC in CP/CPPS patients is significantly reduced. Patients with CP/CPPS have functional activation in the right anterior insula. Pain significantly impacts the anterior insula in CP/CPPS patients, with altered functional connectivity between the motor cortex and the PI. The higher the local efficiency of the left PCUN, the worse the pain symptoms in CP/CPPS patients. The network efficiency ratio was greater in STG patients than in healthy individuals, and STG was involved in the memory bias associated with experimental pain memory.The present systematic review has some limitations. The studies included were nonrandomized controlled trials, and due to the limitations of the study design, selection and measurement bias could not be avoided. The contribution analysis of ALE suggested that cluster 1 was provided by S1, S3, and S4, of which S3 had a high contribution; Cluster 2 was provided by S2, S4, S5, and S6, of which S4 and S6 had a high contribution; S8 and S9 have not made any contribution between cluster 1 and cluster 2 . This maDespite the high prevalence of pain in CP/CPPS patients, current neuroimaging studies provide only a limited understanding of pain mechanisms. There is ample opportunity to advance our understanding of CP/CPPS-related pain mechanisms and future CP/CPPS treatment. More attention should be paid to these brain regions with targeted studies on targeted drugs for pain relief in CP/CPPS. The use of functional and advanced structural MRI techniques to compare differences between CP/CPPS patients and healthy individuals has the potential to advance research in this critical area.


Hemiplegic shoulder pain is the most common complication after stroke. It usually occurs during the critical period of stroke recovery and hinders the rehabilitation of upper extremity motor function. However, there are few studies on the risk factors, the development and prognosis of shoulder pain after stroke.This study aimed to observe the prevalence of post-stroke shoulder pain in the middle-aged and elderly population, find out the risk factors for post-stroke shoulder pain, and explore its effect on stroke outcome.Eligible patients with hemiplegic shoulder pain in the rehabilitation unit were recruited and followed up at 2 and 4 months. The basic clinical information including age, gender, hypertension and atrial fibrillation history, stroke types, stroke location was recorded. Range of motion for shoulder, glenohumeral subluxation, muscle tension, activity of daily living of upper limb were measured. Data from blood test and shoulder ultrasonography were collected.480 stroke patients were screened within 1 year, and 239 patients were included in the statistical analysis. The prevalence of hemiplegic shoulder pain was 55.6% (133/239) at admission, 59.4% (142/239) after 2 months, and 55.1% (130/236) after 4 months. We found that shoulder pain was more likely to occur in women, patients with large-area stroke, increased tension of biceps brachii or triceps brachii, subluxation and limited passive range of motion of the shoulder. And the ability of daily living of patients with shoulder pain was significantly lower than that of patients without shoulder pain. Shoulder ultrasonography showed that the most common lesion in patients with shoulder pain was supraspinatus tendon thickening, and the thickness of supraspinatus tendon in the hemiplegic side of patients with shoulder pain was significantly higher than that of unaffected side. In addition, the hospitalization rate of patients with shoulder pain after 2 months and 4 months was significantly higher than that without shoulder pain.Hemiplegic shoulder pain has a high prevalence and can last for several months. Multiple risk factors are involved. Moreover, hemiplegic shoulder pain affects the readmission rate of patients. Therefore, we should pay more attention to this problem in our clinical work. The application of various means to relieve shoulder pain will be conducive to the recovery of upper limb motor function and shorten the in-hospital rehabilitation time. Hemiplegic shoulder pain (HSP) is the most common complication of stroke patients and has a high incidence rate of 24–64% in the inpatient rehabilitation unit . ShouldeHSP is generally considered to be the result of multiple factors, including mechanical and neurological factors. Mechanical factors include gleno-humeral subluxation , rotatorMany treatments can be used to relieve shoulder pain after stroke. Traditional treatment methods include pills, electrical stimulation , kinesioPrevious studies of HSP have mostly been retrospective, with a large span of young age, and a lack of objective data , 13, 26.From October 1, 2020 to October 31, 2021, any patient hospitalized in the Ruijin rehabilitation ward with stroke was screened. The first evaluation was performed within 1 week after admission, and the evaluation mainly included shoulder pain questionnaire and relevant clinical physical examination see . After 2After screening, we conducted a shoulder pain questionnaire survey, which mainly included: whether there was shoulder pain; Visual Analog Scale (VAS) score of shoulder pain; site of shoulder pain, whether shoulder pain occurred before stroke ; time of pain initiation, frequency of pain; the relationship between shoulder pain and movement; whether shoulder pain affected sleep , 31.We collected the following basic clinical information, including: age, gender, history of hypertension and atrial fibrillation, time of onset, type of stroke , hemiplegic side, stroke area and location . “Undefined” refers to specific stroke location not identified due to lack of examination and reporting.We conducted clinical physical examination to measure the passive range of motion of shoulder joint  , palpatiConsidering shoulder pain may be associated with infection, immune , diabetePatients with HSP were followed up and evaluated at 2 and 4 months of systematic rehabilitation. For readmitted patients, the follow-up evaluation content was the same as the first. While shoulder pain questionnaires were administered to inpatients elsewhere, outpatients and home-based rehabilitation patients. We have dedicated evaluators to do the assessments and ultrasonography were conducted by ultrasound doctor, and all of them were not informed of patients' grouping.The data were statistically analyzed by IBM SPSS statistics 24 software. Using chi square test , we examt-test ; moderate: vitamin D3 ; severe: vitamin D3 <20 nmol/L, and tested their relationship with shoulder pain, respectively. When we used RFrom October 1, 2020 to October 31, 2021, all patients admitted to the Rehabilitation ward of Ruijin Hospital diagnosed with stroke underwent preliminary screening . A totalInitial assessment was performed within seven days of admission, and 133 (56%) of the 239 suffered from HSP. Most patients suffered shoulder pain after stroke. Ten patients reported a history of shoulder pain before stroke, and 8 of them worsened after stroke. Seventy eight (64%) of the 230 patients reported pain herself/himself, and other patients were detected by caregivers or assessors. One hundred and four (85%) shoulder pain occurred after shoulder movements or exercises, and 50 (30%) shoulder pain occurred at rest. At follow-up I, 59% (133-3+12)/239) patients suffered shoulder pain . At follow-up II, 55% (133-3-13+12+4)/236) patients suffered shoulder pain  .Our study reported 239 patients who had initial and two follow-ups data, with an average age of 70 ± 9 years old, ranged from 50 to 94 years, 148 (62%) male, 197 (82%) infarcts, 115 (48%) left hemiplegic, 201 (84%) comorbidity with hypertension, 31 (13%) comorbidity with atrial fibrillation, 27 (11%) large-area cerebral infarction, 38 (16%) cortical cerebral infarction, 34 (14%) brain stem infarction, including 20 (8%) pontine infarction, 35 (15%)basal ganglia infarction, 9 (4%) thalamic infarction, 8 (3%) undefined .2 = 3.895, P < 0.05), patients with large-area infarction  were more prone to develop shoulder pain at initial assessment. However, there was no significant correlation between shoulder pain and age, comorbidity of hypertension, comorbidity of atrial fibrillation, stroke type, hemiplegic side, cortical infarction, brainstem infarction, basal ganglia infarction and pontine infarction.By comparing the baseline clinical factors between the two groups, we found that female patients , especially increased biceps / triceps muscle tension. However, we didn't find an association between shoulder pain and decreased biceps/triceps muscle tension .We found that a greater proportion of patients in the group with shoulder pain (53%) had biceps brachii or triceps brachii muscle tone dystonia than those without shoulder pain (23%) after stroke, and shoulder pain was significantly associated with dystonia . We found a relationship between shoulder pain and restricted shoulder PROM in terms of mild, moderate and severe incidence   of patients with shoulder pain, which was significantly higher than that in patients without shoulder pain (χ< 0.001) .t = −5.418, P < 0.001), grooming , feeding  and bathing   .We found that most stroke patients had elevated SAA and ESR, as well as vitamin D3 deficiency, regardless of whether they had shoulder pain. Vitamin D3 deficiency was present in 83% of stroke patients, with a mean value of 36.5 nmol/L vitamin D3 in serum, while 16% of stroke patients had severe deficiency. 61% of stroke patients had increased ESR, with a mean value of 29.6 mm/h in serum. 71% of stroke patients had increased SAA with a mean value of 34.9 mg/L. However, we did not find a significant correlation between shoulder pain and elevated SAA and ESR and vitamin D3 deficiency. There was also no significant difference in fasting blood glucose, 2 h postprandial blood glucose and glycosylated hemoglobin between patients with shoulder pain and those without shoulder pain .t = 6.197, P < 0.001)  of HSP patients developed supraspinatus tendinitis, 66% (51/77) of HSP patients developed tendinitis of the long head of biceps brachii and 24% (18/77) of HSP patients suffered from SA-SD bursitis . Tendon < 0.001) .We found that the rehospitalization rate of patients with HSP was 84% (112/133) at 2 month of follow-up I, and 59% (77/130) at 4 month of follow-up II, compared with 62% (66/106) and 34% (36/106) of patients without shoulder pain, respectively. Comparing to patients with HSP, patients without shoulder pain were more likely to return to their families. 38% (40/106) of patients without shoulder pain returned to home at 2 months of follow-up, compared with only 14% (19/133) of patients with shoulder pain. At 4 months of follow-up, the proportions of patients without shoulder pain and those with shoulder pain who returned home were 62% (67/106) and 35% (47/133), respectively .In this study, we tried to observe the prevalence of post-stroke HSP in the middle-aged and elderly population, find out the risk factors associated with HSP, and investigated the effect of HSP on stroke outcomes. We found that 56% of stroke patients admitted to the rehabilitation ward suffered from HSP. We observed that HSP last for a long time once it developed. The prevalence of HSP was 59% at 2 months follow-up and 55% at 4 months follow-up. Female, large-area stroke, elevated biceps/triceps tone, subluxation and limited shoulder movement are the risk factors for HSP. Age, history of hypertension, history of atrial fibrillation, stroke type, hemiplegic side, cerebral cortex stroke, brain stem stroke, basal ganglia stroke, thalamic stroke, blood glucose level, inflammatory markers, and vitamin D3 were not significantly associated with HSP. Shoulder ultrasonography showed that 69% of patients with HSP had supraspinatus tendinitis, 66%had long head of biceps brachii, and 23% had SA-SD bursitis. We also found that the thickness of supraspinatus tendon on the hemiplegic side was significantly higher than that on the unaffected side in patients with HSP. Besides, patients with HSP had significantly lower self-care ability and significantly longer hospital stay, comparing with patients without shoulder pain.Due to medical level, stroke duration, study design and other factors, different studies have obtained prevalence of HSP. Previous studies , 29, 39 Our study found that female patients were more likely to develop HSP. However, previous studies showed that shoulder pain was not associated with gender. In one study , it was Ratnasabapathy et al.  found thOur study is the first to observe the relationship between shoulder pain and different stroke location. By collecting the cranial imaging examination report of patients at the onset of stroke, and comparing the proportion of different stroke location between two groups, it is found that the incidence of shoulder pain in patients with large-area stroke is higher. Complications and seriously damaged motor function, which can lead to shoulder pain, usually occurs in patients with large-area stroke. Isaksson et al.  of SwedeSpasticity is closely related to hemiplegic shoulder pain. Our study found that patients with elevated biceps/triceps tone have a higher incidence of shoulder pain. Flexor spasm of upper limb after stroke is manifested in shoulder adduction and pronation . The tonA mount of studies found that some treatments, which can alleviate muscle spasm, such as botulinum toxin injection, shock wave therapy and surgical therapy, can significantly cure spasm and shoulder pain. A systematic review  suggesteWe found that patients with subluxation are more prone to develop shoulder pain. However, the relationship between glenohumeral subluxation and hemiplegic shoulder pain is controversial. After stroke, the muscles around the shoulder are weak and can't effectively resist gravity. There is an obvious gap between the acromion and the humeral head, which is called glenohumeral joint subluxation. The change of the position of the humeral head makes the soft tissue around the shoulder easy to be damaged , resultiFrom the perspective of molecular, our study first observed the relationship between HSP and serological indicators such as blood glucose level, vitamin D3, ESR and infection indexes. It was found that there was no significant difference in fasting blood glucose, 2 h postprandial blood glucose, glycosylated hemoglobin, vitamin D3, ESR and infective situation between patients with shoulder pain and patients without shoulder pain.Diabetes is related to a variety of musculoskeletal diseases. Hao et al.  found thVitamin D3 deficiency is considered to be associated with chronic pain . When thThe soft tissue about shoulder of stroke patients is prone to be injured, which can activate the repair mechanism of the human body and start the inflammatory response. At present, a newly prospecting bioactive therapy called platelet rich plasma therapy can promote the inflammatory response and activate a variety of growth factors. It is applied to patients after rotator cuff tear surgery to promote rotator cuff repair . So we gIn addition, HSP may also be related to poor motor function, paresthesia, and CRPS in hemiplegic limb, which were not focus on in this study. Meta-analysis  suggesteShoulder joint ultrasonography provides an objective basis for the etiological diagnosis of shoulder pain. In our study, GE logiqe9 instrument was used to perform shoulder joint ultrasonography for patients with shoulder pain. The results showed that 69% of patients had supraspinatus tendinitis and 66% of patients had tendinitis of the long head of biceps brachii, which was the most common lesion in patients with hemiplegic shoulder pain. The thickness of supraspinatus tendon of hemiplegic side in patients with shoulder pain was significantly higher than that of healthy side. This is the first study of quantitative analysis of shoulder lesions in patients with hemiplegic shoulder pain using shoulder ultrasonography findings.Different studies have different research samples, inspection instruments and observation indicators, therefore the conclusions are different. Lin PH  retrospeWe found that shoulder pain reduced quality of life, which may hinder the improvement upper limb motor function in stroke patients. Adey-Wakeling et al.  measuredThis is the first study to use shoulder ultrasonic findings to make quantitative analysis of shoulder joint lesions in patients with hemiplegic shoulder pain. There is no objective quantitative data in previous studies. Shoulder joint ultrasound is of great significance in the etiological diagnosis of hemiplegic shoulder pain. From multi-dimensional aspects such as molecular, structural and functional, we observed comprehensive risk factors of hemiplegic shoulder pain. Involving some objective data, the information is more reliable, which is a relatively novel place of this study.From the perspective of rehabilitation, our study observed the evolution of the incidence of shoulder pain over time after systematic rehabilitation treatment. This is the first cross sectional study of hemiplegic shoulder pain in a specific age population and followed up after rehabilitation treatment. The age range of previous studies was large, ranging from about 20 to more than 90 years old. And many indicators observed in the study are elderly-age-related. Our study observed the middle-aged and elderly people, all over the age of 50, which excluded the interference of risk factors of young stroke.However, our study has some limitations. First, most of our data were collected from rehabilitation scales and lacked sufficient quantitative and objective measures, which may introduce some bias to evaluation. Second, we defined post-stroke shoulder pain as occurring and persisting for lasting more than 48 h. At present, there is a lack of uniform criteria for the definition of HSP. In fact, the degree of shoulder pain is one of the important factors we should consider. This may affect the grouping of patients with shoulder pain. Third, this study is a single-center study with a limited sample size, and the applicability and generalizability of the findings will be limited. Finally, ultrasonography examination was performed only in patients with shoulder pain, and it is difficult to find a direct relationship between imaging and clinical impairments. Tendinitis and bursa effusion seen in this study may be associated with older age rather than stroke. In future studies, we will apply objective measures and increase interventions, and increase sample size to carry out multicenter clinical trials to identify risk factors for HSP. At the same time, we will compare images from stroke patients with shoulder pain, stroke patients without shoulder pain, and healthy controls to find a direct relationship between images and injuries.Our study found that hemiplegic shoulder pain has a high incidence and can last for several months. Female, large-scale stroke, elevated muscle tone, subluxation and limited shoulder movement may be important risk factors for hemiplegic shoulder pain. Shoulder joint ultrasound has certain value in the diagnosis of HSP. In addition, HSP increases the readmission rate of patients to some extent. Pain relief may better promote the recovery of upper limb motor function and shorten the in-hospital rehabilitation time.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. The patients/participants provided their written informed consent to participate in this study.JW and QX: conception and design of the study and data confirmation. YL: data collection, analysis of data, statistical analysis, and drafting the manuscript. SY: data collection and analysis. LC, YB, LG, and HP: acquisition of data. All authors contributed to the article and approved the submitted version.


Chronic pain and depression affect millions of people worldwide, and their comorbidity tends to exacerbate the severity of each individual condition. Intersecting brain regions and molecular pathways could probably explain the unique yet complex bidirectional relationship between these two disorders. Recent studies have found that inflammatory reactions, frequently identified in both chronic pain and depression, stimulate certain enzymes in the kynurenine pathway, while concurrently suppressing others. Kynurenine, a major tryptophan derivative, and its metabolites have been implicated in several inflammation-associated pain syndromes and depressive mood disorders. Due to inflammation, 95% of tryptophan is metabolized via the kynurenine pathway, which drives the reaction towards the production of metabolites that have distinct roles in the pathophysiology of these disorders. Diminished levels of the neuroprotective metabolite, kynurenic acid (KYNA), and elevated levels of the neurotoxic metabolite, quinolinic acid (QUIN), have been frequently identified in human patients formally diagnosed with these disorders, as well as animal models commonly used in medical research. This review not only explores the epidemiology of comorbid chronic pain and depression, but also highlights the involvement of kynurenine and its metabolites, specifically KYNA and QUIN, in these pervasive conditions. Chronic pain is defined as persistent or intermittent pain that lasts for more than three months , and is Clinical studies have revealed bidirectional relationships between chronic pain and depression; pain is associated with the persistence of depression, and depression is associated with persistent pain. This bidirectional relationship can potentially be explained by the major molecular pathways that transpire in both conditions, which will be explored throughout this article.A 2019 study by Orhurhu et al. analyzed the National Inpatient Sample (NIS) dataset from 2011 to 2015 and used the ninth and tenth revisions of the International Classification of Diseases (ICD-9 & ICD-10) to identify 9.3 million patients with a diagnosis of chronic pain. Out of these 9.3 million patients, 2.2 million (22.9%) were diagnosed with comorbid depression. The majority of these 2.2 million patients were female 67.5%) and the mean age was 59, with the highest proportion of patients with comorbid depression falling between 45 and 64 years of age. Additionally, patients in zip codes within the lowest income quartile had the highest proportion of comorbid depression (31%), while those in zip codes within the highest quartile had the lowest proportion of depression 16.8%) [7.5% and % [7.5% ap < 0.001) [p < 0.001) [Several studies have revealed an increased prevalence of pain among patients with depression, and vice versa. Rayner et al. studied 1204 chronic pain patients attending an initial consultation at a specialized pain treatment center, and found that 60.8%  met the criteria for mild, moderate, or severe major depressive disorder (MDD)  as asses< 0.001) . They al< 0.001) —than tho< 0.001) . These fOther studies have also identified associations between severity of pain and severity of depressive or anxiety symptoms. De Heer et al. analyzed data from the Netherlands Study of Depression and Anxiety (NESDA), a longitudinal study of 2981 patients recruited from the community, primary care providers, and specialized mental health care facilities . Each paAnalysis of the results showed that having a depressive or anxiety disorder increased the patient’s odds of experiencing highly disabling and severely limiting pain (CPG 4). A total of 80% of patients with CPG four pain also had a current diagnosis of depression (14.3%), anxiety (13.5%), or both (52.1%). Of the 170 patients (5.7%) reporting no pain symptoms (CPG 0), 48% had no psychopathology and 19.4% had a remitted disorder. Those with comorbid depressive and anxiety disorders were least likely to report no pain symptoms. Among those with pain, the highest odds ratios were seen in comorbid depression and anxiety . These fThe complex relationship between chronic pain and depression and anxiety has been thought to be at least partially related to the pathophysiological pathways they share. Recent studies have found considerable overlap in the regions of the brain involved in mood management and the sensing of injury and body pains, including the prefrontal cortex (PFC), insular cortex, anterior cingulate, amygdala, hippocampus, and thalamus . DecreasTissues can be damaged in many ways, namely infection, trauma, oxygen deprivation, chemicals, and heat; each of these pathways leads to inflammation. Once inflammation is initiated, a cytokine cascade follows. There are many molecular mechanisms that take place downstream of this pathway, which ends in the brain . Interac+) from ingested Trp, illustrated in + synthesis. Several of kynurenine’s metabolites also have neurotoxic and neuroprotective effects in response to inflammation, which play a key role in both chronic pain and depression [The kynurenine pathway in particular has been a point of interest due to its involvement in both chronic pain and psychiatric disorders. Kynurenine is a metabolite of the aromatic ring amino acid, tryptophan (Trp), and is produced in the pathway synthesizing nicotinamide adenine dinucleotide (NADpression . For inspression . This arpression .+). In this pathway, indoleamine 2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine and is upregulated by pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). Kynurenine is further metabolized to (1) neuroprotective kynurenic acid (KYNA) via kynurenine aminotransferase (KAT), (2) 3-hydroxykynurenine (3-HK) via kynurenine-3-monooxygenase (KMO), or (3) anthranilic acid via kynureninase. Further metabolism occurs to 3-HK by kynureninase, producing neurotoxic quinolinic acid (QUIN). Recent studies have implicated decreased levels of KYNA [The kynurenine pathway is the main route of tryptophan metabolism, producing the end-product nicotinamide adenine dinucleotide , suggesting that low Trp levels are associated with higher pain intensity. However, there was a significant positive correlation between the kynurenine/Trp ratio and pain intensity (p < 0.001), suggesting that higher kynurenine levels are associated with increased pain. This confirms that most Trp is metabolized in the kynurenine pathway in cases of inflammation-induced pain [Previous clinical studies have identified an association between excessive IDO levels and inflammation-induced pain. As previously mentioned, IDO is the main enzyme in the kynurenine pathway that converts Trp to kynurenine and other active metabolites. Staats Pires et al. found that IDO levels and kynurenine/Trp ratios were significantly higher in patients with back pain compared to healthy controls . A diffeced pain .However, Trp is also needed to produce the neurotransmitter serotonin ,30,31. ANot only is the kynurenine pathway involved in chronic pain, but it has also been found to be involved in psychiatric disorders. A meta-analysis conducted by Ogyu et al. revealed that: (1) both KYNA and kynurenine levels were decreased in patients with depression compared with healthy controls, (2) ratios of both KYNA/QUIN and KYNA/3-HK were lower in patients with depression compared with healthy controls, and (3) there were no differences in QUIN and 3-HK levels between the two groups. These findings suggest that the kynurenine pathway plays a vital role in depression. Ample evidence suggests there is increased inflammation in patients with depression, and the reduced KYNA/3-HK ratio in patients with depression further confirms this, suggesting that the KMO pathway is activated as a result of depression . AdditioQUIN is also considered to be a major contributor to depression by acting on the hippocampus. As one of the limbic structures involved in mood and behavior, the hippocampus cannot synthesize QUIN; however, it possesses NMDA receptor 2A and 2B subtypes, which have a very high affinity for QUIN. Consequently, QUIN can have neurotoxic effects on the hippocampus and promote depression. This neurotoxicity can be displayed as energy dysfunction, oxidative stress, transcription factors, cytoskeletal disruption, behavioral changes, and cell death . Anotherp = 0.015) [There is an ample amount of research exploring chronic pain and depression comorbidity in patients, with the aim of understanding the pathophysiology of both conditions and possibly explaining the reason for this highly prevalent comorbidity. In a retrospective observational study conducted by Pope et al., 298 chronic pain patients were given the patient reported outcomes measurement information system (PROMIS) survey, followed by a urine test prior to beginning therapy. The survey assessed many domains, such as fatigue, pain interference, physical function, sleep disturbance, anxiety, depression, and ability to participate in social roles and responsibilities. Pain intensity was measured with the numeric rating scale (NRS) which was also included in the survey. The urine test was used to investigate pain biomarkers and their relationship with the domains assessed in the survey. The results showed that this population had worse pain than the general population, and they displayed a tendency toward depression, anxiety, fatigue and sleep disturbances. Additionally, 87.2% of all patients had at least one abnormal biomarker in their urine. The most notable of all biomarkers was QUIN, one of the key metabolites of the kynurenine pathway. KYNA was also elevated in 33% of these patients and was strongly associated with pain interference (= 0.015) .Groven et al. studied 48 patients with chronic fatigue syndrome, 58 fibromyalgia patients, and 54 healthy controls, and they examined kynurenine and its metabolites in their blood plasma. When compared with healthy controls, patients with chronic fatigue syndrome had lower KYNA/QUIN ratios, and patients with fibromyalgia had lower ratios of KYNA/3-HAA. This finding suggests that their symptoms could be attributed to a lack of neuroprotective metabolites . Other sInvolvement of the kynurenine pathway and its metabolites has also been identified in patients with schizophrenia, another psychiatric disorder. Schizophrenia is often associated with depression and anxiety and has also been found to be associated with decreased pain sensitivity, although 27% of patients report somatizations that closely correlate with emotional distress. Patients with schizophrenia also display different sensory perceptions, manifesting as insensitivity to hot or cold-induced pain. Depression and anxiety in these patients are closely related to somatic symptoms, such as pains, aches, and flu-like malaise. Many of these findings are attributed to low-grade inflammation and IDO pathway activation. One study recruited 84 patients with schizophrenia and 40 healthy controls, diagnosing schizophrenia according to DSM-IV-TR criteria . InterviHowever, brain tissues from 45 postmortem patients with depression that were found to have reduced inflammation, marked by low levels of TNF-α and IFN-γ, demonstrated less activity in the kynurenine pathway. These findings suggest that inflammation plays a key role in activating this pathway; the presence of depression without inflammation is not sufficient to upregulate kynurenine metabolism. In addition, the majority of kynurenine activity was noted in the ventrolateral prefrontal cortex (VLPFC) ,40. FutuPreclinical studies have also shown consistent results in animal models of depression, despite the lack of clarity on how representative animals can be when it comes to depression and anxiety. Upon inducing inflammation with LPS, cytokine production was increased, and IDO mRNA was seen in microglia. In addition to these molecular findings, LPS administration also elicited depressive-like behaviors in animal models after inducing acute sickness, which later disappeared, while depression persisted. C57BL/6J Mice infected with Mycobacterium bovis, Bacillus Calmette-Guérin (BCG) displayed depressive-like symptoms and increased Trp catabolism via the kynurenine pathway for an extended period of time . A similOlder literature has shown that intracerebroventricular injections of LPS and TNF-α are sufficient to produce depressive-like symptoms in rats. Hippocampal injections of TNF-α in a stereotaxic surgery on rats were deemed to be sufficient to increase thermal hypersensitivity for three weeks post-surgery and allodynia between 12–21 days after surgery. However, administering cytokine antagonists was found to be effective at combating these symptoms . In one Other studies have found that inhibiting IDO or IFN-γ can be effective at protecting against depression. Presence of the IDO enzyme is essential to induce depression-like symptoms. As previously mentioned, IFN-γ is one of the main activators of IDO. In mice that are IFN-γ deficient (IFNγR mice), IDO is not activated, and thus the mice are protected against depressive-like symptoms, despite the induction of an inflammatory response upon inoculation with BCG ,45. Zhang et al. investigated the effect of ketamine injections on pain-induced depression in SD rats. The rats were injected with Freund’s adjuvant to elicit allodynia, depression, and hyperalgesia, which were later confirmed by mobility and sucrose preference tests. Fourteen days later, one group of rats was injected with 1 mL ketamine (20 mg/kg), while the other group was injected with 1 mL saline as a vehicle treatment. Results showed that one injection of ketamine was effective at reducing allodynia and immobility time and increasing sucrose preference. These findings suggest that ketamine has an effect on treating the comorbidity of inflammatory pain and consequent depression. In this same study, hippocampal levels of IDO, kynurenine, and Trp were evaluated upon the administration of ketamine. Results showed that both IDO and the kynurenine/Trp ratio were decreased due to the ketamine injection, suggesting that pain-relieving and antidepressant effects were achieved via the kynurenine pathway . Ido1−/− mice were included in the study, and surgery was performed to obtain spared nerve injury as a model for neuropathic pain. The surgery resulted in decreased social interaction and increased immobility time, confirming depression-like behavior in mice. Although results showed that this induction of inflammation did not lead to an increase in IDO in the brain, there was a significant increase in the liver. Consequently, higher kynurenine levels and kynurenine/Trp ratios were only observed in the plasma, and not in the hippocampus or the frontal cortex, providing interesting findings compared to the study that did find significant increases in hippocampal tissues. Mice that did not have IDO expression did not show a decrease in social interaction and an increase in immobility following the spared nerve injury, suggesting that this enzyme is necessary for the expression of this behavior. However, the test showed that they still developed allodynia, showing that the lack of IDO is not enough to prevent pain [Zhou et al. also conducted a study to investigate the effect of IDO on depression and comorbid pain. C57/BL6J and ent pain .Millions around the globe suffer from comorbid chronic pain and depression. Elucidating the molecular pathways involved in both of these conditions is critical in developing effective treatments and improving patient outcomes. Upon exploring the literature on chronic pain and depression, inflammation was found to be a crucial factor in both morbidities. Further investigation of inflammation pointed to the kynurenine pathway, one of the dominant sequela of Trp, an essential amino acid. The kynurenine pathway is extensive, producing many metabolites that have different reactions in various regions of the body and brain.As highlighted throughout the article, kynurenine levels and kynurenine/Trp ratios were consistently elevated in patients with depression and chronic pain, and they were also noticeably abnormal in animal studies. Regarding the metabolites of kynurenine, KYNA was deemed to be neuroprotective, and was regularly found at lower levels in those same patient populations. On the other hand, QUIN was found to be neurotoxic, especially to the hippocampus, and was abnormally elevated in the plasma of patients with depression and chronic pain. However, it was not only the metabolites that played a role in these morbidities. The IDO enzyme also elevated kynurenine levels, which likely led to certain metabolites, notably QUIN, being produced in excess, while others, such as KYNA, were suppressed. IDO was found to be stimulated by inflammation, demonstrating another link between the kynurenine pathway and the pathogenesis of these morbidities. Overall, a pattern was observed in all studies involving depression and chronic patients: elevated QUIN levels and decreased KYNA levels. Future studies might consider investigating the role these specific metabolites can play in the treatment of these common morbidities.