The aim of this multicenter randomized interventional prospective study was to compare the ultrasound (US)-guided lumbar medial branch block (LMBB) with the fluoroscopy (FS)-guided LMBB in terms of analgesic efficacy and disability in the setting of the treatment of pain arising from the lumbar facet joints (LFJ).Fifty adults with a “LFJ” syndrome were randomized into two groups: in group FS, fluoroscopic-guidance was used to block the medial branch at three lumbar levels ; in group US, same blocks were performed under ultrasound. Needle transverse approach was used with both techniques. Effects of these procedures were assessed with a Visual Analogue Pain Scale (VAPS), the Oswestry Disability Index (ODI) and the Duke’s Activity Status Index (DASI) scale, before the treatment, 1 week and 1 month after. Hospital Anxiety and Depression Scale (HADS) score was also collected before the procedure. Analysis of variance, one (for non-inferiority) and two-sided Mann-Whitney tests and Chi-square tests were performed.P = 0.047) in terms of VAPS, ODI and DASI at 1 week and 1 month. Duration of techniques and HADS were similar between groups .LMBB under US-guidance was not inferior to FS-guidance (The medial lumbar bundle branch block under ultrasound-guidance is not inferior to the fluoroscopy-guidance procedure in effectively alleviating pain arising from the facet joints. Considering that this ultrasound technique has the benefit of an irradiation-free, real-time procedure, it can be considered as an effective alternative to the fluoroscopy-guided technique. Lumbar facet joints (LFJ) syndrome is a common source of spinal suffering affecting up to 45% of patients with a chronic low back pain (LBP) because of inflammation, degenerative or arthritic changes, overload of the posterior LFJ or muscle imbalance –6. It caIn fact, it cannot be identified by imaging or physical examination alone, because of various presentations  and referred pain, making the diagnosis complicated , 7, 8.The first-line therapy for the alleviation of chronic LBP of zygapophyseal joint origin includes bedrest, oral analgesics/anti-inflammatory drugs and physical therapy. If unsuccessful, intra-articular injections and lumbar medial branch block (LMBB) can provide diagnosis and are always performed prior to the neurotomy (radiofrequency or cryoneurolysis) which is able to provide short and long-term pain relief –6, 9–13.According to pain centers, LMBB is realized by fluoroscopy (FS), ultrasonography or computed tomography (CT) scanner for guidance . The curThe aim of the present study was to prospectively compare the effectiveness of those two imaging-guided techniques regarding the early and long term pain scores.This prospective multicenter randomized controlled trial was conducted from 6 January 2021 until 10 March 2022 in three pain management centers in Brussels (Belgium); Saint-Pierre University Hospital (César de Paepe site), Erasme and Braine-l’Alleud Hospitals. This open label study was approved by the three Ethics Committees of ULB  and was registered on the publicly accessible Clinical Trial Registry .All participants received and signed an informed consent before the infiltration including all the information about the procedure, the benefits and the possible risks . Allocation concealment was achieved using opaque numbered sealed envelopes, opened only after each patient’s arrival in the operating theatre, in each center. Patients beneficiated the FS or the US technique, according to the randomization and both the attending anesthetist and the patient were aware of the allocated technique. All patients enrolled in the study were requested to report to investigators the evolution of the applied scores variables by phone at the predetermined time points.Inclusion criteria: patients aged between 20 and 80 years old, having a chronic LBP compatible with a LFJ syndrome for at least 3 months without response to a conservative treatment of minimum 4 weeks.2 have not been included because of a predisposition to early degeneration of articular structures and the risk of bad visualization by US, the resolution decreasing with the depth of the fat layers.Exclusion criteria: refusal to participate to the study, pregnant or breastfeeding women, allergy to injected products (Methylprednisolone (Depomedrol) or Lidocaine (Linisol)), psychiatric disorders hindering understanding of the protocol, local or systemic infection or coagulation disorder. In addition, patients should not present any sign of dissociated pain, radiculitis, neurological diseases , spinal instability or deformities , history of lumbar surgery, fracture or lumbar tumor. Further, patients with a body mass index (BMI) > 35 kg/m.For this study, the investigators have blocked the LMBB on three lumbar levels  performed under US versus FS according to a transverse approach. The aim was to compare the equivalence of these two modalities by the evaluation of the benefit of the procedures on pain with a Visual Analogue Pain Scale (VAPS), the evolution of the possibility of carrying out daily activities with the Duke’s Activity Status Index (DASI) and the limits of daily activities with the Oswestry Disability Index (ODI). Scores were collected before injection, 1 week and 1 month after. Hospital Anxiety and Depression Scale (HADS) before the procedure was also filled to detect anxiety and depressive disorders in the setting of the treatment of pain arising from the lumbar facet joints. Moreover, duration of the procedures, incidence of adverse events, work status and medications were obtainedPatients were positioned in prone position with a pillow under the stomach to facilitate the view of the structures by compensating the lumbar lordosis. After disinfection of the lumbo-sacral region with alcoholic chlorhexidine 0,5%, an infiltration was performed in three puncture points unilaterally  with a 22-gauge spinal needle in the transverse plane. At each level, 1 mL of a mixture consisting of 3 mL of Linisol 2% (60 mg of lidocaine) plus 1 mL of Depomedrol 40 mg/Lidocaine 10 mg was injected. The procedure time was recorded from insertion to removal of the needle. The ultrasound devices used were different between the centers; C6–2 probe of the Sparq ultrasound system  at César de Paepe Hospital, C1–5 probe of the Logiq S8 ultrasound system  at Erasme and Braine-l’Alleud Hospital. The scopies used were also different; Ziehm brand  at César de Paepe and Siemens brand  at Erasme and Braine-l’Alleud Hospitals. It should be noted that thermocoagulation was performed after 2 weeks on patients at the Braine-l’Alleud hospital.In the US group, once the spinous processes of the lower lumbar vertebrae were located, with a convex probe with the mark on the cranial side Fig. , the proIn the FS group, The C-shaped arm of a X-ray fluoroscopy was positioned around the patient in an antero-posterior view tilted ¾ in order to see the classic view called “scotty dog”. The puncture point was determined by the positioning of the needle with the so-called “tunnel vision”. The needle was thus brought to the bone contact corresponding to the eye of the scotty dog in tunnel vision, corresponding to the area of passage of the lumbar median branch.The primary endpoint was to investigate the non-inferiority of the US group, comparing to the FS group in regard to the evolution of the ODI measured 1 month after the LMBB. Power analysis was performed with a projected standard deviation of 7. If there was truly no difference between the standard and experimental treatment, then 50 patients are required to be 80% sure that the lower limit of a one-sided 95% confidence interval  will be under the non-inferiority limit of + 5 points. Analysis of non-inferiority was realized with a one-sided Mann-Whitney test.All data for the ODI, the VAPS and the DASI measured before, 1 week and 1month after the LMBB were compared by an analysis of variance for repeated measures with mixed models with treatment arms, time, thermocoagulation status, time x treatment interaction, thermocoagulation status x time interaction and time x treatment x thermocoagulation status interaction terms.2 test and the other continuous non-longitudinal variables such as HADS were compared with the Mann–Whitney test. Data were presented as mean ± SD or number (%). For all tests, a P value less than 0.05 was considered statistically significant. All analyses were performed using the NCSS 21.0.4 statistical package .Categorical data were compared by a χInvestigators screened 64 patients during the study period. Of them, 50 patients who answered to the phone call participated until the end of the study and were considered for the per protocol analysis Fig. .Fig. 2Ilp = 0.34). Both techniques improved VAPS, ODI and DASI at any time without statistical difference between both groups (p > 0.05) (Table p = 0.047) (Table Patients’ characteristics were shown in Table s p > 0.0 (Table pp = 0.046), with a smaller, although not significant (p = 0.08- Bonferroni test) mean value for VAPS after 1 month in patients with thermocoagulation. This led us to suspect a possible effect of thermocoagulation on VAPS after 1 month. However, the treatment group x thermocoagulation x TIME interaction was not significant (p = 0.69) showing that the evolution of the VAPS values over time in both treatment groups was identical whatever the thermocoagulation status , which has a major socio-economic impact and sometimes leads to a sedentary lifestyle causing muscle weakness, eliciting a vicious circle of risk of chronic pain , 12, 17.As a reminder, five vertebrae constituting the lumbar spine are separated anteriorly by the discs which can be a source of pain and posteriorly by the LFJ also called zygapophyseal joints, composed of the superior articular process and inferior articular process. Between these articular processes, lies the synovial membrane, a hyaline cartilage covered by the fibrous capsule within the lumbar spine Fig.  4, 14]., 14.4, 1LMBB is a diagnostic block but can sometimes be considered as therapeutic due to 3.5 months average pain relief of LBP and the significant improvement in functional capacity , 9. If tLocal anesthetics were injected since it blocks the sympathetic reflex arc and the axonal transport inside nerve fibers. Furthermore, it suppresses nociceptive discharge with anti-inflammatory effect. In addition, we use corticosteroids for their anti-inflammatory, immunosuppressive and anti-edematous effects with an inhibitory action of neuronal transmission in the C fibers , 12.2, it is preferable to use fluoroscopy when there is poor visualization due to deeper layers.Even if US-guidance does not clearly detect a foraminal extent and an intravascular injection, these complications have also been described with the technique by FS-guidance . RecentlAs limits to our study, we note a small population sample with an age variability implying anatomical distinctions, a relatively short follow-up of 1 month and the different ultrasound and fluoroscopy machines between the centers. More, patients often have other complaints than pain unilateral LFJ syndrome : this lack of homogeneity is certainly unavoidable when considering the types of patients who visit pain clinics. Also, patients report changes in VAPS levels over the course of the day and according to their activities so all of that biases the rating scales. Although thermocoagulation is performed after 2 weeks at Braine-l’Alleud Hospital, it has no influence on the comparison between the two techniques.Despite the benefit of LMBB, there are few articles comparing imaging methods for this infiltration as well as on improving the quality of life of patients after the procedure, which is essential. For future investigations, we propose the comparison of LMBB performed by FS versus US with the US-guidance in a longitudinal axis  which requires only one puncture instead of three, which would be an advantage for patient (faster and less painful) . FurtherThe present study shows that the medial lumbar bundle branch block conducted using ultrasound-guidance is not inferior to the fluoroscopy-guidance procedure in terms of pain relief and functional improvement. Considering that ultrasound has similar benefits, is a non-irradiating technique, easier to handle and allows real-time manipulations, it should be considered as an adequate and safe alternative to the fluoroscopy-guided technique.


This study aimed to compare the analgesic effects of Ibuprofen and bromelain after periodontal surgery.  A double-blinded crossover clinical trial was conducted on 22 patients needing two crown lengthening surgeries without bone surgery or with limited bone surgery on two quadrants of the maxilla, with control and test sides. Each quadrant was randomly assigned to bromelain (500 GUD) or ibuprofen (400 mg). Immediately after the surgery and 6 hours after it, the first dose of the drugs was packaged in the same capsules in A and B. Postoperative pain was evaluated during the first 8 hours and on the following day using a visual analog scale (VAS). P=0.047). In contrast, there were no significant differences between the two groups at 2, 6, 8, 10, 12, 24, and 48 hours (P>0.05). Using the VAS, the Ibuprofen group showed significantly lower mean pain scores than the bromelain group at 4 hours ( The effectiveness of bromelain for pain control following periodontal surgery was comparable to that of Ibuprofen. Therefore, bromelain can be an efficient replacement for ibuprofen in managing pain after periodontal surgery, especially in patients with gastric ulceration and increased bleeding tendency. This pain can be an example of acute dental pain with mild to moderate severity.1 Two types of cyclooxygenase (COX-1 and COX-2) have been identified.4 COX-1, a structural component in many tissues of the body, results in homeostasis in the body by producing prostaglandins. Its main functions include protecting the gastrointestinal tract, increasing renal function, affecting the central nervous system, and increasing the circulatory system’s permeation.6 COX-2, an inducible form, produces prostaglandins that mediate the inflammatory response and pain-signaling transmissions. It is initially responsible for producing prostaglandins which accelerate vasodilation, increase vessel permeability, and decrease pain threshold.7 Conventional non-selective nonsteroidal anti-inflammatory (NSAIDs) drugs such as ibuprofen inhibit COX-1 and COX-2.5 Although this drug significantly improves inflammation and pain, its long-term use has side effects, such as gastric and renal toxicity. For this reason, selective inhibitors of COX-2 have been developed to reduce these side effects.6 Bromelain is a water-based product derived from the stem and fruit of pineapple with plenty of proteolytic enzymes, whose composition varies depending on the source and purification method. Bromelain directly affects mediators of pain such as bradykinin. Also, the analgesic and anti-inflammatory properties are closely interrelated. It has been shown that this fibrinolytic element increases the absorption of edema by blood circulation. This element reduces swelling, bruising, pain and duration of postoperative healing after trauma or surgery. Evidence has shown that bromelain removes edema by fibrin degradation. In addition, bromelain inhibits the synthesis of pro-inflammatory prostaglandins, especially prostaglandin E2.10 Bromelain is used instead of NSAIDs in patients with osteoarthritis.11 Many inflammatory mediators are released after damage to periodontal tissues.12 evaluated the effect of oral bromelain versus oral diclofenac sodium with placebo on pain, quality of life, swelling, and trismus after the surgical removal of impacted lower third molars. The individuals who had used diclofenac and bromelain had considerably lower mean pain scores than those using a placebo. Bromelain’s effect on postoperative pain was comparable to that of diclofenac sodium. Zatuchni and Colombi13 evaluated the effect of bromelain on the pain intensity of episiotomy and showed that the severity of pain, inflammation, and edema in individuals treated by bromelain was significantly lower than in the group using a placebo, and wound healing was faster in these individuals. Hotz et al14 evaluated the efficacy of bromelain in reducing postoperative pain and swelling. They reported an important anti-inflammatory and anti-edematous effect of bromelain. According to statistical analyses, the inflammatory responses in the group treated with bromelain were significantly less than the control group. Majid and Al-Mashhadani15 to assess the efficacy of bromelain in controlling edema and its related pain in the inflamed area after upper third molar exodontia, the effectiveness of bromelain in treating postoperative edema after third molar surgery was reported. In another study by Inchingolo et al The present study investigated the effect of bromelain on pain relief after periodontal surgery using a prospective, double-blind clinical trial to select a suitable drug for pain relief in these patients. This study received approval from the Human Research Ethics Committee of Tabriz University of Medical Sciences under the code IR.TBZMED.REC.1395.496. This randomized, double-blind crossover clinical trial was conducted on 22 patients (12 men and 10 women) aged 35‒50 years from those referring to the Department of Periodontics, Faculty of Dentistry, Tabriz University of Medical Sciences. All the patients were selected according to inclusion and exclusion criteria. The entire study process was explained to the patients. All the patients agreed to participate by signing a written informed consent form that thoroughly explained the steps of the study. The clinical trial registration number of this research was IRCT201608301760N46. This study was performed on patients needing two crown lengthening surgeries on both quadrants of the maxilla. To match the two surgical areas as much as possible, patients without bone surgery or with minimum bone surgery were included in the study, and the surgeries were performed by one surgeon. The investigation was designed, analyzed, and interpreted according to the Consolidated Standards of Reporting Trials (CONSORT) . The exclusion criteria were as follows: any sensitivity to these two drugs or other nonsteroidal anti-inflammation drugs, asthmatic patients, heart disease history, pregnancy, patients with indigestion systemic diseases like peptic ulcers, renal or hepatic diseases, coagulative disorders, patients with severe anxiety during dental visits, patients taking analgesics in the previous 48 hours, patients > 50 years of age, individuals using alcohol and addictive drugs.16 Since anxiety varies from one patient to another and may affect their pain severity, patients were asked to complete Modified Dental Anxiety Scale (MDAS) questionnaire. This questionnaire includes five questions and five answers for each question. Each item has five answers, and the range of answers is from “not anxious” to “extremely anxious.” The responses are scored from 1 to 5 in ascending order in terms of increasing intensity of dental anxiety. By rating all five items, the total score of all questions for the scale will vary from 5 to 25. The cutoff score of ≥ 19 indicates patients with high dental anxiety or possibly dental phobia. Ibuprofen (400 mg)  and Anaheal GDU 500  were prepared as the drugs needed for this study. Each capsule of Anaheal contains 200 mg (500 GDU) bromelain (2500 GDU/g). The two medications were poured into similar capsules and coded into groups A and B by a pharmacologist (PZ). For each patient, two surgeries were conducted in two different jaw quadrants with a 4-week interval. Patients underwent crown lengthening by one resident of periodontics (AM) with sufficient experience.17 The VAS was presented to the patients as a 10-cm ruler, with the point at the left end of the VAS range representing complete analgesia and the point at the right end representing the highest pain imaginable. Patients expressed their pain severity by marking a point somewhere between the two end points at 2, 4, 6, 8, 10, 12, 24, and 48 hours postoperatively, which was recorded in the relevant forms. For ethical purposes, acetaminophen codeine was prescribed for all the patients as a supplementary analgesic. The patients were justified to use it only if they had intolerable pain. Only patients who needed crown lengthening of maxillary teeth were selected to unify the study groups and eliminate possible confounding factors during surgery in various parts of the oral cavity. The duration of surgery in this study was 45‒60 minutes; otherwise, the patients would be excluded. All the surgeries were performed in the morning. The surgeon was allowed to use two capsules of 2% lidocaine with 1:100 000 epinephrine for each patient. The patients consumed group A drug 1 hour before the first surgery and then every 6 hours. Likewise, they used group B drug for the second surgery. The patients’ pain intensity was evaluated 2, 4, 6, 8, 10, 12, 24, and 48 hours after the surgery using visual analog scale (VAS).P < 0.05. The data were analyzed using SPSS 17.0 using descriptive statistics (means and standard deviations). The differences between the two groups were analyzed using the Mann-Whitney U test for independent samples at a significance level of  The total number of patients was 22 (12 men and 10 women) with 44 quadrants, with a mean age of 45.82 ± 2.8 years. All the participants completed the study, and no side effects were reported for each drug. In addition, the amount of local anesthesia used, the type and extent of surgery, and the duration of surgery were the same for all the subjects.P < 0.05).18 Many drugs with different mechanisms have been introduced to prevent or reduce pain. One of the most common drugs for pain control is NSAIDs which reduce pain by inhibiting prostaglandins.19 Recently, a new analgesic agent, referred to as bromelain, has been marketed in capsule form. It is extracted from the root of pineapple fruit. Several studies have supported the usefulness of oral administration of bromelain in controlling pain and swelling after surgery.20 It has been shown that bromelain has analgesic and anti-inflammatory properties in addition to its antithrombotic, anti-edematous, and fibrinolytic effects. Experimental evidence shows that bromelain’s anti-inflammatory function is mediated through several factors: by increasing serum fibrinolytic activity, reducing plasma fibrinogen levels, and decreasing bradykinin levels, which lead to reduced edema and pain.21 It is believed that the analgesic properties of bromelain are due to its direct effect on pain mediators such as bradykinin and its indirect anti-inflammatory function, including a reduction in edema, debris, and immune complexes, which leads to pain relief.23 Postoperative pain is unpleasant. Trauma and tissue damage during surgery lead to the destruction of cell membranes and the release of phospholipids that turn into prostaglandins, thromboxane, and other metabolites through COX-1 and COX-2 enzymes, ultimately causing pain.24 Therefore, in the present study, we tried to match the subjects enrolled regarding age, gender, anxiety, type, and duration of surgery. Since anxiety varies from one patient to another, the patients were asked to complete the MDAS questionnaire.25 Subjects whose total scores were > 19 were excluded. The present randomized, double-blind crossover study was designed to compare the analgesic effects of bromelain with a commonly used analgesic agent, ibuprofen 400 mg, to evaluate the possibility of using this drug as an alternative to ibuprofen to decrease its side effects. The intensity of the pain depends on several factors, including the type of dental treatment, such as endodontic treatment or periodontal surgery, the type of periodontal surgery, the duration of surgery, the psychological condition of the patient, the patient’s gender, and the extent of tissue trauma during surgery.12 evaluated the effects of bromelain and Diclofenac sodium on pain relief after the surgical removal of third molar teeth. Both groups showed significant pain relief compared to the placebo group. In the present study, the severity of pain 4, 6, 8, 10, 12, 24, and 48 hours after the surgery (based on VAS) was not significantly different between the bromelain and ibuprofen groups. The main finding was that bromelain’s analgesic effects were similar to ibuprofen, which could justify using bromelain as an alternative to NSAIDs. These findings are consistent with other studies in this respect. Majid and Al-Mashhadani15 compared bromelain (40 mg every 6 hours for 6 days) with ketoprofen (100 mg every 12 hours for 6 days) and found no differences between them, concluding that bromelain is as effective as NSAIDs in relieving postoperative inflammation. In addition, de la Barrera-Núñez et al26 evaluated the effect of bromelain administered orally in the postoperative pain control after removing impacted lower molars. All the patients in this study received the rescue medications. However, the test group was administered three tablets of bromelain per day during the first three days and two tablets per day from the fourth to the seventh day. The control group was given a placebo. There were no statistically significant differences between the treatment groups. The differences between studies might be primarily due to a lack of knowledge of the effective dose of bromelain indicated for postoperative pain control. It has been demonstrated that the effect of bromelain is dose-dependent. The benefits of bromelain have been demonstrated at a small dose of 160 mg, but in most conditions, the best results are achieved at doses of 750‒1000 mg/d in four divided doses.27 However, the results of the present study showed that pain intensity four hours after surgery in the bromelain group was significantly more than in the ibuprofen group. This finding can be attributed to the pharmacokinetic differences between the two drugs. Ibuprofen acts centrally and peripherally, inhibiting cyclooxygenase in the brain and peripheral tissues. Its maximum effect is achieved at a dose of 400 mg. An oral dose of 400 mg is rapidly absorbed and reaches a peak plasma level in 30‒60 minutes. Its half-life in the plasma is 1.6‒2.5 hours.28 According to the plasma concentration curve, there is an average of 10.8 µg of bromelain for 3‒51 hours. The estimated plasma half-life was 6‒9 hours.29 This pharmacokinetic difference between the two drugs can justify the severity of pain two hours after surgery for bromelain versus ibuprofen. When ibuprofen is taken postoperatively, the plasma concentration is expected to be below optimal levels 5‒6 hours after dosing.30 On the other hand, Inchingolo et al31 In this study, pain intensity was recorded for the first 8 hours and on the day after surgery. An 8-hour period seems appropriate for pain intensity assessment because it properly covers the duration of action of both drugs. There is also evidence that pain levels after periodontal surgery are the greatest within the immediate 11-hour postoperative period. Our study was limited by a small number of participants. Nevertheless, this study highlights the need for further large-scale and long-term clinical trials to examine the efficacy of bromelain in pain relief. In addition, it is suggested that further studies be carried out to evaluate the side effects of these two medications after periodontal surgeries. Bromelain is an efficient alternative to ibuprofen to manage pain after periodontal surgery, especially in patients with gastric ulceration and increased bleeding. Additional studies with a larger sample size and different doses of bromelain are recommended to determine a better medication. None. The raw/processed data required to reproduce these findings can be shared after publication by requesting from the corresponding author. Adileh Shirmohammadi is the editor-in-chief of JAPID at the time of publication. The authors declare that they have no other competing interests with regards to authorship and/or publication of this work. This study received approval from the Human Research Ethics Committee of Tabriz-Iran University of Medical Science under ethics number IR.TBZMED.REC.1395.496. Not applicable.


Background: Globally, alternative medicine is used widely by most patients for several health challenges. To evaluate the effectiveness and safety of PeaNoc XL Tablet in managing pain and inflammation, a randomized clinical trial and systematic study was designed. PeaNoc XL Tablet has been widely utilized for pain and inflammation management, but no previous studies have examined its efficacy and safety. The aim of this study was to determine the clinical effectiveness and safety profile of PeaNoc XL in patients with arthritis experiencing joint pain and inflammation.Methods: A randomized, controlled, and an open-label trial was conducted. A total of 155 patients (18 to 60 years) with arthritis were enrolled for participation. Using computer-generated random sequences, the study population was divided into two groups in a randomized manner. Group A received Standard therapy and Group B received Standard therapy with PeaNoc XL Tablet 400mg (two tablets OD after food).Results: Out of 155 patients, a total of 83 individuals were excluded from the study, leaving 72 patients who were randomly assigned to either Group A (n=36) or Group B (n=36). The administration of PeaNoc XL as an adjunct to standard therapy resulted in a significant reduction in levels of TNF-α (P<0.01), IL-1β (P<0.001), IL-6 (P<0.01), and CRP (P<0.01) in arthritis patients experiencing joint pain and inflammation. Conversely, no notable differences were observed from the baseline in the standard therapy group.Conclusions: After 12 weeks of supplementation of PeaNoc XL tablets, as an add-on therapy helps in the reduction of pain score, joint stiffness, and physical stiffness.Trial registration:  CTRI/2022/10/046693. Alternative medicine, encompassing herbal medicines, phytonutrients, ayurvedic products, and nutraceuticals, is commonly employed by a substantial number of patients worldwide to address diverse health conditions. According to available data, approximately 80% of the global population relies on herbal products as their primary choice of treatment for various ailments. The utilization of alternative medicines, including classical herbal products, has exhibited a consistent and notable upward trend over the past few decades.PeaNoc XL Tablet is extensively utilized for the purpose of pain and inflammation management. PeaNoc XL Tablet is a combination of palmitoylethanolamide 400mg and astaxanthin 1mg. These mechanisms are associated with the alleviation of allodynia and hyperalgesia in the neuropathic pain model.Palmitoylethanolamide (PEA) is an endogenous fatty acid amide belonging to the class of lipid mediators and the family of N-acylethanolamines (NAEs). It shares similarities with the endocannabinoid anandamide (AEA). PEA demonstrates inhibitory effects on the release of pro-inflammatory mediators from activated mast cells and diminishes mast cell activation at nerve injury sites. Carotenoids, including astaxanthin, are recognized for their antioxidant properties and have gained significant attention for their therapeutic advantages in conditions related to aging and various diseases.Astaxanthin is a carotenoid primarily present in natural sources and marine organisms, including microalgae, salmon, trout, krill, shrimp, crayfish, and crustaceans.To the best of our knowledge, there is no scientific study investigating the efficacy and safety of PeaNoc XL in arthritis patients. Therefore, a clinical trial was conducted to assess the clinical efficacy and safety of PeaNoc XL specifically in arthritis patients experiencing joint pain and inflammation.1.To evaluate the efficacy of PeaNoc XL tablets on biochemical parameters in arthritis patients with joint pain and inflammation.2.To evaluate the efficacy of PeaNoc XL tablets on inflammatory cytokines in arthritis patients with joint pain and inflammation.3.To assess the efficacy and safety of PeaNoc XL tablets in relation to the arthritis Index (WOMAC) in arthritis patients with joint pain and inflammation.4.To evaluate adverse drug reactions in the study period.A randomized, controlled, open-labelled trial was conducted at a SRM Medical College Hospital and Research Centre in Tamil Nadu.CTRI/2022/10/046693.The study adhered to the guidelines set forth by the International Committee on Harmonization on Good Clinical Practice and followed the revised version of the Declaration of Helsinki. Approval for the study protocol was obtained from the institutional human ethics committee of SRM Medical College Hospital and Research Centre on March 25, 2022, with Ethics Clearance No: 8275/IEC/2022. The study is registered with the Clinical Trials Registry India (CTRI) under the reference numberPeaNoc XL Tablet contains astaxanthin (1mg) + palmitoylethanolamide (400mg)Direction: two tablets once daily (OD)•Eligible participants diagnosed with arthritis, regardless of sex, in the age range of 18 to 60 years (inclusive).•Patients with a DAS 28 (Disease Activity Score) score greater than or equal to 3.2•Voluntary willingness to provide written informed consent for participation.•Ability to comprehend the nature and objectives of the study and demonstrate a willingness to adhere to study procedures.•Participants taking other non-steroidal anti-inflammatory drugs (NSAIDs)/painkillers other than standard drug•Abnormal results on liver function test•Patients with diabetic neuropathy•Patients with severe renal, hepatic, cardiac, gastrointestinal, neurological, hematological, or respiratory disorder•Patients with a psychiatric disorder•2 or <20 kg/m2BMI >35 kg/m•Participants who were likely to have surgery during the study period•Participants who have partaken in any clinical study or clinical trial in the previous 12 weeks•Known hypersensitivity to the study drugs•Patients with severe infection•History of intake of any ayurvedic/herbal/homeopathic/dietary supplements in the last two months•Pregnant or nursing mothers and women of childbearing age refusing to use contraceptivesIn this pilot study conducted over a duration of nine months, a sample size of 30 patients was divided into two groups. Group A received standard therapy for the specified condition, while Group B received standard therapy in addition to PeaNoc XL Tablet 400mg, taken orally after food.Group A: Standard therapyGroup B: Standard Therapy + PeaNoc XL Tablet 400mg (2 Tablets OD after food)Study Duration - nine monthsSample size - Pilot sample (30 patients in each group) as per WHO guidelinesThe included study populations based on study criteria were randomized into two groups by using a computer-generated random sequence in R software. Group A received Standard therapy and Group B received Standard therapy with PeaNoc XL Tablet 400mg (two tablets OD after food). questionnaire was assessed subjectively before and after the treatment to evaluate the efficacy of the PeaNoc XL supplementation.The hematology, liver, and kidney functions were evaluated for both groups. The levels of inflammatory cytokines, including TNF-α, IL-1β, IL-6, and CRP, were measured using the enzyme-linked immunosorbent assay (ELISA) technique. Western Ontario and McMaster Universities Arthritis Index (WOMAC)Morning blood samples of 5mL were collected via venous puncture from participants who had fasted overnight, specifically between the hours of 8:00 a.m. and 10:00 a.m. Following collection, centrifugation was performed using an Eppendorf Centrifuge 5430R. The resulting samples were divided into aliquots and stored at -20°C until analysis. All biochemical tests were conducted using a fully automated clinical chemistry analyzer  with ERBA diagnostics kits (ERBA Diagnostics Mannheim GmbH).The levels of TNF-α, IL-6, IL-1β, and CRP were quantified utilizing a two-step sandwich-type immunoassay known as the Human Leptin Quantikine ELISA Kit, which incorporates enzymatic amplification.1.Pain (five items): while walking, using stairs, in bed or rest, sitting or lying, and standing upright2.Stiffness (two items): after the first walk and later in the dayPhysical Function (17 items): climbing stairs, walking, rising from a sitting position, standing, bending down, moving in or out of a vehicle, shopping, putting on or taking off socks, rising from bed, lying in bed, getting in or out of the bath, getting on or off the toilet, doing heavy domestic duties, or light domestic duties.The WOMAC pain scale is extensively used in the evaluation of hip and knee osteoarthritis (OA). It is a self-managed questionnaire consisting of 24 items divided into three subscales, as follows:▪None (0),▪Mild (1),▪Moderate (2),▪Severe (3), and▪Extreme (4)The results of the questions are scored on a 0-4 scale:▪0-20 for Pain,▪0-8 for Stiffness, and▪0-68 for Physical Function.The scores for each subscale are added up, with a possible score range ofHigher scores on the WOMAC signify worse pain, stiffness, and functional limitations.A total number of 155 patients were assessed for admissibility, while 83 patients were excluded. In the end, 72 patients were included and were randomized into two groups. Group A received Standard therapy and Group B received standard therapy with PeaNoc XL . The basIn the Standard therapy group (Group A), two patients were lost to follow-up due to non-response to phone calls. In the Standard therapy group + PeaNoc XL group (Group B), one patient was lost to follow-up due to migration. Thus, 34 patients’ data were analyzed in Group A and 35 patients’ data were analyzed in Group B  and3.Patient demographics were recorded for both groups after receiving informed consent. In the baseline assessment, no significant differences (P>0.05) were observed between age, BMI, hip circumference, waist circumference, platelets, blood, and biochemical parameters among the groups .Blood samples were obtained from the patients at the beginning of the study (baseline) and at the end of the three-month period for both study groups. These samples were collected to conduct liver and kidney function tests, which included the analysis of various parameters such as total bilirubin, direct bilirubin, total protein, albumin, globulin, serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), and serum creatinine.Results showed that PeaNoc XL tablets did not influence any of the parameters. Thus, the safety of the PeaNoc XL is established with the biochemical parameters as shown inThe values are presented as mean±SD. Significance levels are denoted as follows: P<0.01* (significant), P<0.05** (significant), and P<0.001*** (highly significant).The levels of inflammatory cytokines, including TNF-α, IL-6, IL-1β, and CRP, were assessed using the ELISA technique. The addition of PeaNoc XL to standard therapy resulted in a significant reduction in the levels of TNF-α (P<0.01), IL-6 (P<0.01), IL-1β (P<0.001), and CRP (P<0.01) among patients experiencing joint pain and inflammation. In contrast, the standard therapy group did not exhibit any notable difference compared to the baseline levels of these cytokines.WOMAC questionnaire has three main areas such as pain score, joint stiffness, and physical stiffness. The addition of PeaNoc XL as an adjunct therapy demonstrated significant reductions in pain (P<0.001), joint stiffness (P<0.01), and physical stiffness (P<0.001) compared to baseline among patients with joint pain and inflammation. In contrast, standard therapy did not exhibit statistically significant differences in these parameters in the same patient population.Safety assessmentFollowing a 12-week treatment with PeaNoc XL therapy, all hematological and biochemical safety parameters remained within normal ranges. No severe adverse side effects were reported during the study period, and none of the patients withdrew their consent due to adverse drug reactions.PEA is a bioactive lipid mediator resembling endocannabinoids that falls within the NAE fatty acid amide family. It is ubiquitously present in various tissues, including the brain. PEA is thought to be synthesized in response to cellular injury as a pro-homeostatic protective mechanism and its production is enhanced in disease conditions. PEA exhibits diverse effects, encompassing anti-inflammatory, analgesic, antimicrobial, antipyretic, antiepileptic, immunomodulatory, and neuroprotective properties.The multifaceted mechanisms of action exhibited by PEA offer potential therapeutic advantages in various disorders, including allergic reactions, the common cold, chronic pain, joint pain, and neurodegenerative conditions. Additionally, PEA has been shown to enhance muscle recovery and improve cognition, mood, and sleep.PEA presents itself as a promising alternative for the relief of joint pain. A clinical trial employing a triple-blind, randomized, parallel-arm design revealed that PEA exhibited superior efficacy in reducing temporomandibular joint (TMJ) OA pain when compared to ibuprofen.In a double-blind, randomized, placebo-controlled trial, the efficacy of PEA in patients with mild to moderate knee OA was established. Over the course of an eight-week clinical study, patients who received a high-bioavailability form of PEA demonstrated dose-dependent improvements in joint pain, stiffness, and function, as evaluated using the WOMAC questionnaire. Notably, joint pain decreased by 40% with a 300 mg PEA dosage and by 49.5% with a 600 mg PEA dosage, accompanied by a significant decrease in the use of rescue medication by the end of the eighth week. These findings highlight the potential of PEA as a novel treatment for alleviating pain and related symptoms associated with knee OA.The available studies, along with the existing literature, highlight the intriguing potential of PEA as an alternative treatment for addressing joint pain.Astaxanthin, a red carotenoid pigment present in diverse plant and marine organisms like shrimps and salmon, exhibits a range of biological functions. Notably, it is recognized for its potent antioxidant, anti-inflammatory, and anti-cancer properties.A study has provided evidence supporting the potential beneficial effects of astaxanthin in the context of OA. Notably, astaxanthin demonstrated significant reductions in the activities of MMP-1, MMP-3, and MMP-9, as well as inhibited the expression of MMP-1, MMP-2, MMP-9, and MMP-13 in various cell types. These findings are particularly valuable in terms of inhibiting matrix degradation. Consequently, the study suggests that astaxanthin holds promise as an agent with anti-osteoarthritic properties.The findings of the present randomized, open-label interventional trial showed that PeaNoc XL tablets help in the reduction of pain, joint stiffness, and physical stiffness (WOMAC questionnaire).Inflammatory levels of TNF-α, IL1-β, IL-6, and CRP levels in patients with joint pain and inflammation were significantly reduced in PeaNoc XL add-on treatment as compared to baseline and standard therapy.A 12- week supplementation of PeaNoc XL add-on therapy was effective in arthritis patients with joint pain and inflammation.PeaNoc XL was well-tolerated as an add-on oral therapy, suggesting its safety and efficacy.This randomized study showed that adding PeaNoc XL Tablet to standard therapy effectively reduced pain, joint stiffness, and physical stiffness in arthritis patients. It also resulted in significant reductions in inflammatory markers. PeaNoc XL Tablet demonstrates potential as a safe and effective option for managing joint pain and inflammation in arthritis patients.All authors, including K. N. Nandakumar, Dr. E. Caston, Dr. R. C. Satish Kumar, Dr. T.M. Vijayakumar, S. V. Vishagan, Pankaj Negi, and A. Sukkur, made equal contributions to this report. They had full access to all the data in the study and took responsibility for ensuring the integrity and accuracy of the data analysis.Study design: K. N. Nandakumar, Dr. E. Caston, Dr. R. C. Satish Kumar, Dr. T.M. Vijayakumar, S. V. Vishagan, Pankaj Negi, and A. Sukkur.Study supervision: K. N. Nandakumar, Dr. E. Caston, Dr. R. C. Satish Kumar, Dr. T.M. Vijayakumar, S. V. Vishagan, Pankaj Negi, and A. Sukkur.: K. N. Nandakumar, Dr. E. Caston, Dr. R. C. Satish Kumar, Dr. T.M. Vijayakumar, S. V. Vishagan, Pankaj Negi, and A. Sukkur.Acquisition, analysis, or interpretation of data This paper is done very accurately and very useful for clinical practice. Pain relief is very important, this paper reflects the proper usage of peanoc-xl and the potency of the medication. The generated data will be useful for future doctors to use the medicine in treating different chronic painful conditions.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Orthopaedics, pain managementI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Adding PeaNoc XL Tablet to standard therapy effectively reduced pain, joint stiffness, and physical stiffness in arthritis patients. It must be supplemented for all backpain & arthritis patients. This study adequately shows the effectiveness of PeaNoc XL tablets as an adjunct for chronic pain management in arthritis patients. PeaNoc XL tablets, as an add-on therapy helps in the reduction of pain score, joint stiffness, and physical stiffness.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:pain managementI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


Chiropractors’ clinical indicators for recommending preventive continued care to patients with low back pain include previous pain episodes, a history of long pain duration and improvement after initial treatment. Our objectives were, in a cohort of patients with neck pain, to examine whether these clinical indicators were associated with being recommended continued care beyond 4 weeks, and if so whether this recommendation was dependent of chiropractor characteristics, as well as if the number of clinical indicators influenced this recommendation.In this multi-center observational study, 172 patients seeking care for a new episode of neck pain in chiropractic practice in Norway were included between September 2015 and May 2016. The chiropractors treated their patients as per usual, and for this study, baseline data and 4-week follow-up data were used. Patient data included the clinical indicators (1) previous episodes of neck pain, (2) a history of long duration neck pain and (3) improvement four weeks after initial treatment. The recruiting chiropractors were asked at 4-week follow-up if each patient was recommended continued care, defined as care planned beyond the first 4 weeks. Univariate and multivariable logistic regression models investigated the association between clinical indicators and the continued care recommendation, as well as the influence of chiropractor characteristics on this recommendation. Cross tabulations investigated the relationship between the number of indicators present and recommendation of continued care.Long duration of neck pain was the strongest clinical indicator for being recommended continued care 4 weeks after the initial treatment. Chiropractor characteristics were not associated with this recommendation. In patients with all three clinical indicators present, 39% were recommended continued care. When two and one indicators were present, the percentages of those recommended continued care were 25% and 10%, respectively.Chiropractors recommended continued care for patients experiencing neck pain based on their history of long pain duration, and this was not influenced by characteristics of the chiropractor. This differs from previous studies of indicators for maintenance care in patients with low back pain.The online version contains supplementary material available at 10.1186/s12998-023-00507-y. Neck pain is a common health problem  and mostTo date, the prognosis of neck pain is poorly understood, and no cure exists. For patients that experience recurrent and persistent neck pain that negatively affects daily living, pain management may be the most effective approach to reduce the number and impact of relapses and maintain good function and quality of life. In chiropractic practice, patients with these pain patterns may be recommended maintenance care (MC) , 10. MC previous pain episodes, long pain duration, and have shown improvement after initial treatment [previous pain episodes was found to be a strong predictor for recommending MC [Focus groups and surveys have systematically explored chiropractors’ indications for using MC in patients with low back pain . Accordireatment –21. Thesnding MC . In addinding MC .Most studies on clinical indications and efficacy of MC have been performed in patients with low back pain . One stuSpecifically, the objectives were (1) to investigate whether the clinical indicators identified for low back pain were associated with being recommended continued care for patients with neck pain, (2) whether this recommendation was dependent on chiropractor characteristics, and (3) to examine if the number of identified clinical indicators influenced this recommendation.This study was based on data from a one-year longitudinal observational multicenter cohort study designed to identify clinical course patterns and prognostic factors in patients with neck pain consulting chiropractors in Norway. The Norwegian Regional Committees for Medical and Health Research Ethics (2015/89) approved the study. The study was reported according to the STROBE statement .Chiropractors across Norway were recruited through The Norwegian Chiropractors’ Association’s newsletters, general assembly, and social media groups, there were no specific criteria for the clinic or chiropractor. Those who signed up for the study were given written material and a brief workshop regarding the primary study objectives, inclusion, and exclusion criteria, as well as procedures. A total of 66 chiropractors from 43 clinics in all four Norwegian health regions were recruited, representing urban and rural areas, and each of them recruited 1–11 consecutive patients with neck pain. This broad approach ensured a diverse sample of Norwegian chiropractors and their neck pain patients. Between September 2015 and May 2016, patients who were aged 18 years and older, consulting the chiropractor for the first time with an episode of neck pain with or without arm pain and were fluent in Norwegian, were eligible for participation. We excluded patients with a suspicion of serious pathology . For this study, we used data collected with digital questionnaires at baseline and at 4-week follow-up. The treatment was according to the chiropractor’s choice and included various methods where manipulation and soft tissue techniques were most frequently used. However, this study did not address treatment, and it was up to the chiropractor to determine the appropriate treatment plan. Although there was no blinding of patients or chiropractors involved in the study, the questionnaires were completed independently and without the presence of researchers. More information on the recruitment process, procedures, and the baseline questionnaire  used for the cohort has been previously published –36.The baseline questionnaire included sociodemographic data such as gender  and age (years), pain history and symptom variables  pain-sites). Pain intensity was rated on the numeric rating scale (NRS) . The NecInformation regarding patient’s subjective improvement has, in previous studies been collected during the fourth consultation following the initial treatment , 22. In At baseline, chiropractors reported their gender , age (years), the country for their chiropractic education, and the graduation year. The following countries were used ‘United Kingdom’, ‘Denmark’, ‘USA’, and ‘Australia’. For analyzing, we treated the country of chiropractic education as a categorical variable and used ‘United Kingdom’ as reference. To determine the number of years in practice, we used the graduation year as a proxy and subtracted it from the year for data-collection (2015). We analyzed the number of years in practice as a continuous variable.At 4-week follow-up, the chiropractors answered if further treatment was planned for each patient. The question  included four response options: ‘no further treatment planned’, ‘no further treatment planned but patient will contact when treatment is needed’, ‘yes further treatment planned but patient must contact for continued care’ and ‘yes, appointment(s) have been set up for continued care’. These four categories were dichotomized into ‘no continued care’  and ‘yes continued care’  have been set up for continued care’).Descriptive analyses were used to characterize the study sample, the analyzed study sample and the stratified sample dichotomized by the continued care variable. We used mean values and standard deviations for continuous variables and frequencies for categorical variables. Differences in patients’ characteristics between the dichotomized continued care outcome variable were analysed by t-tests for normally distributed variables and by Chi-squared test for categorical variables.We performed the statistical analyses in three steps consisting of univariate and multivariable logistic regression models : (1) we 2 (0.15) and used overall outcome proportion of 0.5. For logistic models, this specifies a sample size (n) of 103 for these indicators. Our total sample size included 172 patients. Thus, we anticipated that our study would provide meaningful estimates of predictive performance.The outcome parameter was the odds ratio (OR) with 95% confidence interval (CI). An additional outcome measure was discrimination by the Area Under the Receiver-operating Curve (AUC) (with 0.5 representing no discrimination beyond chance and 1 representing perfect discrimination) . Thus, aCross-tabulations were used to investigate how the number of indicators  related to the recommendation for continued care. This descriptive approach enabled an assessment of the association between multiple indicators and the likelihood of recommending continued care.At the 4-week follow-up assessment, four chiropractors failed to complete the questionnaire, resulting in the absence of outcome data for eight patients. We excluded these eight patients from the cross-tabulation and regression analysis, thus our analyzed sample included 164 participants. Importantly, there were no significant differences observed between the chiropractors who completed the 4-week follow-up questionnaire and those who did not, regarding their chiropractic characteristics or the number of patients recruited into the study. Furthermore, no substantial differences were found between the analyzed sample and the excluded patients .Clustering effect in studies happens when patients treated by the same chiropractor have similar outcomes on factors such as characteristics and treatment protocols. Since only a small number of patients were recruited by each chiropractor it deemed unnecessary to conduct multi-level analysis.All analyses were performed in STATA, version 16 .The chiropractors (n = 66) were mainly female (64%), and the mean age was 39 (sd 8) years. Most chiropractors graduated from a chiropractic college in the United Kingdom, and the majority had worked more than 5 years in practise .The study sample included 172 patients with neck pain. After 4 weeks, 37 (23%) had an appointment set up for continued care  for recommending MC to patients with low back pain also applied to patients with neck pain who were recommended continued care beyond 4 weeks. Having a long duration of current neck pain was found to be the only clinical indicator to predict if continued care was recommended to the patient by the chiropractor. However, a recommendation for continued care was not associated with chiropractor characteristics. We found that when all three clinical indicators were present, 39% of patients were recommended to receive continued care. As the number of indicators decreased, the likelihood of the recommendation decreased as well, suggesting the relationship between indicator count and the recommendation for continued care.Our findings indicate that clinical indicators for recommending continued care to patients with neck pain are different from those used for recommending MC to patients with low back pain. A study investigating the rationale for MC in a low back pain population found that patients perceive MC to prevent recurrences and help them remain as pain free as possible . This maA long duration of pain and previous pain episodes are likely to be highly correlated, and a history of long pain duration has been associated with an unfavorable outcome . Thus, iInterestingly, reporting improvement with initial treatment by the fourth week was not found to influence continued care. Thus, despite that improvement with initial treatment has been suggested as an important indication for MC by chiropractors in the Nordic countries , it was The accuracy of the multivariable regression models was examined using the AUC. Overall, the information provided by the indicators allowed continued care to be distinguished from not continued care with a moderate degree of accuracy (AUC = 0.76). Thus, many patients with all three indicators were frequently regarded as not being candidate for continued care. When adding chiropractor characteristics in the model, the AUC increased to 0.80. Even acknowledging that chiropractor characteristics might impact the improved AUC outcome, no statistically significant association between chiropractors and the outcome was found. Moreover, it is important to note that the confidence intervals for the AUC values overlapped suggesting the observed increase from an initial AUC of 0.76 to 0.80 may not be statistically significant. Therefore, the practical significance of this improvement remains uncertain.One study found that the initiation of MC is a shared decision between the patient and the chiropractor . At baseCharacteristics of a chiropractor  will be the same exposures for patients visiting a specific chiropractor, but different from those of another chiropractor. A Danish study found that place of training and number of years in practice were associated with the use of MC . HoweverThe study was a multicenter study gathering data on patients with neck pain from many Norwegian chiropractors, thus likely to reflect clinical practice and result in good external validity. We consider our sample to be representative when compared to previously published work . Our stuWe used digital questionnaires that required all questions to be answered, eliminating the issue of missing data. Our study had a limitation regarding loss to follow-up, as 4% of the included patients lacked information from chiropractors regarding continued care at the 4-week follow-up. This may raise a question about possible attrition bias. To address this, we tried to contact all chiropractors (by phone and/or mail) and ask about reasons for not completing the questionnaire. The primary reason reported was lack of time. There were no obvious differences observed between chiropractors caring for patients with or without information in the analyzed sample. Additionally, the excluded patients without information showed only minimal variations from the analyzed sample, indicating a limited risk for attrition bias to impact the study findings.We tested the associations in both univariate and multivariable models. The sample size (n=164) was considered sufficient to explore the predictive performance and strength of association between three indicators, chiropractor characteristics and outcome . A potenAnother potential limitation is that the chiropractors in the study were not specifically asked whether they considered the individual patient as candidate for MC or if they recommended a preventive approach. The analysis is based on their recommendation of continued treatment. Our results are therefore not directly comparable with those of MC studies. Neck pain is a heterogeneous condition with distinct clinical features and various responses to treatment, so the intent of continued care may have been diverse and not solely preventive. For instance, patients being slow responders to initial care plans may have required extended treatment plans, and as a result, been deemed suitable for continued care. Therefore, patients may have been recommended continued care with different objectives and, not solely preventive. However, we do believe that a recommendation for continued care may serve as a proxy for a MC recommendation.One may argue that a follow-up period of four weeks is too short to consider a continued care approach for patients with low back or neck pain. We found that patients recommended for continued care were more severely affected at baseline and at 4-week follow-up. These patients reported higher pain intensity, a longer pain duration, and a higher number of MSK pain-sites compared to patients not being recommended continued care. One may hypothesize that the chiropractors were sensitive to these hallmarks and identified these patients as a subgroup with a more severe pain affliction. Thus, continued care would be a reasonable option to manage their condition.In patients with neck pain, a long duration of pain was a strong clinical indicator for the chiropractor to recommend continued care. Thus, the duration of neck pain may have important clinical implications.The clinical indicators for recommending continued care to patients with neck pain in chiropractic practice differ from those used when recommending MC to patients with low back pain. We found that the strongest clinical indicator for the chiropractor to recommend continued care was a long duration of neck pain. None of the included chiropractor characteristics had a significant impact on this recommendation. Only 39% of patients presenting with previous neck pain episodes, a history of long neck pain duration and improvement four weeks after initial treatment had an appointment for continued care. Our results suggests that more knowledge is needed about the possible differences in recommending continued care for patients with neck.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2Supplementary Material 3Supplementary Material 4Supplementary Material 5Supplementary Material 6


Medication‐induced mood disorders following epidural steroid injections are possible therefore should be disclosed to the patient.Medication‐induced mood disorders have been rarely reported following epidural steroid injections (ESI). This case series presents three patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5) criteria for substance/medication‐induced mood disorder after an ESI. In considering a candidacy for ESI, the rare but significant, side effects of psychiatric side effects should be disclosed to patients. It is well known mood disorders can affect many facets of a person's life, notably their perception of pain. Conversely, it is also established that pain, whether acute, subacute, or chronic, may also precipitate mood disturbances. The symptoms of mood disorders can include hypomania/mania, depression, anxiety, suicidal ideation, delirium, and psychosis.Chen et al. reported a case of mania following epidural steroid injections (ESI) in a patient without a previous psychiatric history.There are five criteria to meet the DSM‐5 diagnosis for a substance/medication‐induced depressive disorder. These are (1) persistent disturbance in mood characterized by depressed mood or anhedonia, (2) symptoms of depression or anhedonia develop soon after suspected exposure to medication/substance or the involved medication/substance is known to be capable of producing such symptoms, (3) the disturbance is not better explained by another depressive disorder or depressive symptoms resolve after removal of medication/substance, (4) depressive disturbance is not occurring during a time of delirium, (5) the depressive symptoms are causing significant distress in a person's life‐limiting his/her ability to function.2Case one is a 32‐year‐old African American female with no past medical history who presented to the pain management clinic with complaints of pain after a motor vehicle collision occurring 1 month prior to presentation. She reported the pain as being 8/10, radiating to her left buttock and mid‐posterior thigh. Two weeks before the visit, she was prescribed an oral methylprednisolone dose pack for 6 days, which relieved her pain without observed side effects. Her examination was significant for bilateral L5 4/5 weakness with 1/2 sensation to light touch. Magnetic resonance imaging (MRI) of the lumbar spine revealed type one modic changes of the inferior and superior plates of L5 and S1 with a large right central and left central disc protrusion resulting in contact of the bilateral descending S1 nerve roots. She then underwent bilateral L5–S1 transforaminal ESIs with an injectate of 1 mL of 40 mg/mL triamcinolone and 1 mL of 0.25% bupivacaine. She reported nausea and vomiting the day of the injection and insomnia that lasted 6 days. Seven weeks post‐injection, she had mood changes, swelling in her face and hands, polymenorrhagia, and weight gain and was referred to her endocrinology by per primary care provider. Ten weeks post‐injection, she presented to the endocrinology clinic by referral from her primary care provider due persistent weight gain and was subsequently diagnosed with iatrogenic steroid‐induced Cushing syndrome after being found to have an elevated cortisol level. She was referred by her primary care provider to psychiatry 4 months post‐ESI. She was started on sertraline 25 mg titrated up to 50 mg and prazosin 1 mg at bedtime, after having been diagnosed with post‐traumatic stress disorder, severe major depressive disorder (MDD), and panic disorder. The patient was seen by the pain psychology clinic for pain coping strategies. When re‐evaluated by a pain management physician in clinic nearly three and a half years later, she was off sertraline or prazosin without further depression.Case two is a 58‐year‐old caucasian male with a past medical history significant for hypertension who was evaluated by pain medicine for chronic low back pain associated with radicular pain down the left leg. It was later discovered that the patient had a remote history of MDD over 20 years prior treated with venlafaxine and bupropion. His examination was significant for 4+/5 strength in left L4 distribution with left L4 1/4 reflexes. MRI of the lumbar spine revealed lateral recess and foraminal stenosis at L4–L5 and L5–S1 with probable compression of the traversing left L5 and exiting left L4 nerve roots. He underwent a left L4–L5 transforaminal ESI under fluoroscopic guidance consisting of a mixture of 1 mL of 0.5% bupivacaine and 40 mg of triamcinolone. At one‐week post‐injection, the patient reported his mood had severely worsened, similar to a depressive episode he had suffered many years prior. He noted the onset occurred 2 days post‐ESI without any pre‐procedure depressive symptoms. The patient experienced anhedonia and suicidal ideation without a plan. He promptly resumed his former depression treatment regimen of venlafaxine 75 mg daily and bupropion 100 mg daily under the supervision of his primary care physician (PCP). At 3 weeks post‐ESI, the patient reported an 80% improvement in his pain, although his mood remained depressed. At that time, his PCP titrated his bupropion up to 200 mg daily and referred him to a psychologist and psychiatrist. His depressive symptoms fully resolved 3 months post‐ESI.Case three is a 56‐year‐old Hispanic male with a past medical history of depression and anxiety presenting to pain medicine for evaluation of 3 days of mid‐thoracic back pain. He rated the constant, burning pain as 10/10 and stated that it was exacerbated with any movement, specifically back extension. Physical examination was notable for tenderness to palpation in the left thoracic paraspinals and left thoracolumbar facet joint loading. The examination was largely limited due to pain but was without signs of weakness or neurological compromise. MRI of the thoracic spine revealed multilevel discogenic and facet changes throughout the thoracic spine. He underwent a successful T12–L1 interlaminar steroid injection after his insurance denied left‐sided thoracic medial branch blocks. Interlaminar injectate included triamcinolone 80 mg with 3 cc of 1% lidocaine & 5 cc of normal saline. Two days after the injection, he reported new‐onset insomnia. At his follow‐up visit, when asked about his mood, he stated “I am scared” referring to his anxiety, with a concordant generalized anxiety disorder‐7 (GAD‐7) score of 15. To curb his insomnia, he was prescribed a four‐week course of trazodone. It was recommended by the pain management team that he follow‐up with his psychiatrist and other mental health providers. At the three‐month follow‐up, he reported persistent sleep and appetite disturbances with associated weight loss and anhedonia with an inability to return to work due to his mood and pain. By the 5‐month follow‐up, all symptoms had resolved with a GAD‐7 score of 4. His psychiatrist had prescribed citalopram 5 mg daily for the previous 2 months.3ESI‐induced depression may be an overlooked side effect of steroid injections. Mood symptoms may occur more frequently than originally thought as subclinical symptoms may go unreported by many chronic pain patients. Following up on a detailed post‐injection psychiatric history is a challenging endeavor. Many patients have a complex psychiatric history characterized by multiple comorbid psychiatric syndromes that make it difficult to anchor new mood symptoms to an exogenous substance. Kim et al. studied patients with and without depression that had been diagnosed with cervical spondylosis and cervical radicular pain finding a statistically significant difference between groups for reported pain improvement. The non‐depressed group had greater pain improvement documented at all follow‐up checkpoints.Patients who experience pain are predisposed to developing mood disorders. While an in‐depth discussion of the links between pain and depression goes beyond the scope of this paper, the association is likely due to overlapping neural pathways and neurotransmitters, among other similarities that lead to maladaptive neuroplasticity.If signs and symptoms of depression are recognized, a prompt referral to a psychiatrist should be made. If an immediate psychiatry appointment cannot be scheduled, patients should follow‐up with their PCP. If patients report depression with suicidal ideation, they should be urgently directed to the nearest emergency room or crisis center.In case one, during the initial pain management screening, the patient did not endorse depression or anxiety in the clinic screening. When evaluated by psychiatry, steroid‐induced depression was not on the differential diagnosis and the recent ESI was not mentioned in the note. Those with Cushing syndrome can have several neurophysiologic symptoms including depression (37%–86%), anxiety (80%), panic attacks (30%), irritability (8%), insomnia, memory loss, and emotional lability, while mild paranoia and mania are less common.Concerning cases two and three, it is not clear if the patients were screened for a history of mood disorders at their initial evaluations. Both patients' mental health histories were recorded based on intake forms. However, it does not appear that further consideration of previous mood disorders was taken into consideration with ESI planning. It is important to note that his symptoms were not immediately linked to the ESI. In the third case, symptoms were initially masked by the confounding acuity of his pain exacerbation and new‐onset insomnia after the ESI. It was not until the three‐month follow‐up that symptoms seemed to have developed into more easily recognized mood symptomatology including anhedonia, appetite changes, weight loss, and continued sleep disturbance. The latter two cases highlight the value of a pain management physician using a patient health questionnaire‐9 (PHQ‐9), GAD‐7, or a similar screening tool in the initial intake before visits, especially in cases where procedures may be indicated. More so, these screening tools can be used to assess mood‐related side effects in the immediate and intermediate post‐procedure time frames.The authors recognize that pain may precipitate mood dysregulation and may be a cofounding variable in the cases discussed. A definitive causation cannot be attributed entirely due to an ESI, and the association between pain and mood disturbance is acknowledged. Based upon symptom onset and presentation, an ESI may have been one of the precipitants of mood dysregulation in the three cases discussed. Although definitive causation cannot be attributed entirely due to this variable, it appears likely from the symptom onset and presentation that an ESI(s) was the most likely precipitant of mood dysregulation in the three cases discussed. In considering candidacy for ESIs, the rare, but significant side effects of depression or other psychiatric manifestations should be discussed with patients at a minimum during the consent process. This potentially life‐altering side effect should especially be disclosed as part of the informed consent process to those who have had or are currently suffering from depression. A pain management physician should consider pre‐screening patients for risk factors as well as have a management plan that includes prompt referral to psychiatry if psychiatric symptoms are reported by the patient.Christian T Vangeison: Conceptualization; methodology; writing – original draft; writing – review and editing. Joseph p Roys: Conceptualization; methodology; writing – original draft; writing – review and editing. Marissa N Catalanotto: Conceptualization; methodology; writing – review and editing. Wyatt I Kupperman: Methodology; supervision; writing – review and editing. Alexander R Kovacs: Conceptualization; methodology; writing – original draft; writing – review and editing. Dan Sebastian Dîrzu: Supervision; writing – review and editing. Emanuel N Husu: Conceptualization; project administration; supervision; writing – review and editing.The authors have no sources of funding or competing interests to declare for this manuscript.The authors declare no conflicts of interest.Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.


Post-operative pain of endoscopic submucosal dissection (ESD) is always be overlooked and undertreated by endoscopists. However, the incidence of moderate to severe pain after ESD is as high as 44.9% to 62.8%, which can greatly affect the patient’s recovery, reduce their satisfaction, and extend their hospital stay. Transcutaneous electrical acupoint stimulation (TEAS) have been shown to reduce postoperative pain and enhance gastrointestinal (GI) function recovery in patients undergoing abdomen surgery. However, there is no evidence regarding on the effect of TEAS on post-operative pain and complications in patients undergoing ESD. Therefore, we aim to investigate whether perioperative TEAS treatment is superior to the sham acupuncture in terms of post-ESD pain and GI function recovery.This study is a prospective, randomized controlled trail, which is single-blinded and in single center. A total of 120 patients undergoing elective gastric and esophageal ESD surgery in Beijing Friendship Hospital, Capital Medical University, will be involved in this study. These individuals will be stratified according to the type of ESD surgery  and be randomly divided into two groups. L14, PC6, ST36 and ST37 will be stimulated at the TEAS treatment group, and the control group will receive simulation at four sham acupoints. The primary outcome is post-EDS VAS score at the time of entering PACU, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, 6 h, 18 h, 24 h, 48 h after the surgery. The secondary outcomes include the anesthesia-associated parameters, sedation score, nausea and vomiting score, shivering score, recovery of gastrointestinal function, satisfaction of patients to anesthesia, incidence of postoperative complications, QLQ-C30 life quality scale, and the economic indicators.The results of this study will confirm that continuous preventive application of TEAS can alleviate the postoperative pain among patients with gastric and esophageal ESD surgery and accelerate the recovery of post-ESD gastrointestinal function.http://www.chictr.org.cn/showproj.aspx?proj=135892.Chinese Clinical Trial Registry, ID: ChiCTR2100052837, registered on November 6, 2021. The online version contains supplementary material available at 10.1186/s12906-023-04075-9. Endoscopic submucosal dissection (ESD) is a minimally invasive treatment for early gastrointestinal neoplasms, with the advantages of histological en bloc mucosal resection, accurate pathologic diagnosis, low recurrence rate, and fast recovery after surgery –3. HowevPresently, there has been no unified conclusion on how to perform effective postoperative analgesia to patients with gastric and esophageal ESD surgery. Because such patients need to be discharged quickly, overdose of opioids are often not recommended. Some studies found that intravenous dexamethasone or lidocaine, or local infusion of bupivacaine and triamcinolone during ESD procedure can help to relieve post-ESD abdominal pain, while reducing the consumption of intraoperative opioids and decreasing patient body movement –9. HowevAs an important part of traditional Chinese medicine, acupuncture and moxibustion are widely used to regulate organ functions during perioperative period, including the treatment of postoperative pain . TranscuIn our previous study, it was found that preventive continuous application of TEAS can reduce postoperative pain and promote gastrointestinal function recovery in patients undergoing laparoscopic resection of gastroesophageal tumors –16. HoweThis trial has been approved by the Ethics Committee of Beijing Friendship Hospital, Capital Medical University , and has been registered in the Clinical Trial Registry (Chictr) with number: ChiCTR2100052837  of gastrointestinal surgery.n = 60) and the TEAS treatment group . Each group has 30 gastric cases and 30 esophageal cases  at 1:1 ratio and be randomized into two groups: the sham group  will be used to record all the original data needed.We will recruit 120 patients who are scheduled to undergo gastric or esophageal ESD procedure. These participants will be recruited from Beijing Friendship Hospital affiliated to Capital Medical University after they are up to the eligibility criteria and sign the informed consent. We enrolled the first patient on December 1st, 2021, and will end up recruiting on December 30th, 2023. Full communication and some small gifts such as keychains will be provided for patients to encourage the enrollment. All subjects will sign the informed consent form to participate in this clinical trial, allowing the researchers to collect and analyze their data.Inclusion criteria include the following:Aged 18–75 years, diagnosed at gastric or esophageal tumor undergoing ESD procedure, regardless of gender.2 ≤ BMI ≤ 30 kg/m2 [body mass index = weight (kg)/height (m)2].18 kg/mAmerican Society of Anesthesiologists (ASA) classification levels I–III.Participating in the study voluntarily and signing informed consent.Exclusion criteria include the following:Surgical incision or scar in the meridian of the acupoints of Hegu (L14), Neiguan (PC6), Shangjuxu (ST37), Zusanli (ST36).Local skin infection at the acupoints above.Upper limb or lower limb nerve damage.Participating in other clinical studies within the past 4 weeks.Inability to understand the numeric rating scale (NRS) score and the visual analog scale (VAS) score.Application to a pacemaker.Gravida, puerperant and patients with positive urine pregnancy tests.Combined with preoperative pain, using central analgesic drugs, addicted to or dependent on opioids.Preoperative complications including severe CNS diseases or severe mental diseases.Considered not suitable for this study.Discharge criteria are as follows:Requirement for participants to withdraw during the trail.Rejection of administration of remedy medication after surgery.Violation of the test program.Arising of serious adverse events (AEs).Transferred to open surgery.The duration of ESD procedure > 4 h.The following approaches are suggested Fig. :The anesthesiologist will perform preoperative education on patients who meet the inclusion criteria and make sure they can understand and utilize VAS and NRS to evaluate their degree of pain and nausea when patients are admitted into operation room. Explaining to patients of the research purpose, process, risks and benefits, and other related contents. Guaranteeing that they are willing to adhere to trail schedule. Finally, ensuring that self-reported information sheet which is used in postoperative follow-up is issued and the informed consent is signed.Electrocardiogram, blood pressure, pulse oxygen saturation and BIS will be performed.The TEAS or sham stimulation will be conducted by the experienced anesthesiologist and acupuncturist at 30 min before the surgery until the end of the operation.Rapid sequence induction is applied as anesthesia induction strategy. Midazolam 0.03 mg/kg, remifentanil 1-2 μg/kg, etomidate 0.1–0.2 mg/kg and rocuronium 0.6–0.8 mg/kg is used before intubation. When the patients lose their consciousness, mask ventilation is given. Mechanical ventilation will be performed after endotracheal intubation .2 at 35–45 mmHg. The infusion of sedative and analgesic agents are stopped after suture of the operative incision.Anesthesia is maintained with total intravenous infusion of propofol (4-6 mg/kg/h), remifentanil (0.05–0.2 µg/kg/min) and rocuronium (one third of the induced dose every 40 min). Anesthetic depth is controlled by the adjustment of infusion speed of intravenous propofol to maintain a bispectral index at 45–55 during procedure. The analgesia nociception index (ANI) is maintained at 50–70 by regulating the speed of remifentanil intravenous infusion. Respiratory parameters are adjusted to maintain PetCOUnder the premise of maintaining appropriate anesthesia depth, atropine 0.25–0.5 mg at one time is given if heart rate (HR) is under 50 times per minute and esmolol 0.2–0.5 mg/kg is administrated if HR is above 100 times per minute. If the mean blood pressure is below 65 mmHg or decrease by more than 20% of baseline, ephedrine 6 mg will be given. Tramadol 50 mg is applied for analgesia 30 min before the end of ESD surgery.At the end of surgery, patients will be extubated and transferred to the postoperative care unit (PACU) in routine.The Visual Analogue Scale (VAS) will be utilized to evaluate the extent of the pain of patients, and if VAS score ≥ 4 points or the patients asked for analgesia during the follow-up period, morphine 1 mg will be administered intravenously. The Numerical Rating Scale (NRS) is used to evaluate the degree of nausea. If NRS ≥ 7 or vomiting occurs, serotonin 3 receptor antagonist will be given. Concomitant medication administration during the trial period from the beginning of surgery to 2 days after the end will be recorded.Patients in TEAS group will be treated bilaterally at four acupoints: Hegu (L14), Neiguan (PC6), Zusanli ST36) and Shangjuxu (ST37). L14 is the primary acupoint of the hand yangming large intestine meridian, which is located on the dorsum of both hands between the first and second metacarpal bones , and 9 cun above and 1 cun outside HT7 Fig. A. The otThe primary outcome is post-operative pain (VAS) score at the time of entering PACU, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, 6 h, 18 h, 24 h, 48 h after the surgery. The incidence of post-ESD VAS ≥ 4 and the consumption of morphine during follow-up will also be recorded.Anesthesia-associated parameters: The systolic pressure, diastolic pressure and heart rate will be recorded before anesthesia induction, intubation, 30 min, 60 min after the start of surgery, at the end of the surgery and 5 min before and after extubation. The amount of intraoperative sedative and analgesia drugs consumption will be recorded. The time from the end of propofol infusion to the recovery of autonomous respiration, to extubation and to the eye open of patients will be recorded. The occurrence of dysphoria, nausea and vomiting will be also written down.♦ Sedation score: Sedation score after complete awakening will be assessed at the moment of entering PACU, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, 6 h, 18 h, 24 h, 48 h after surgery.♦ Nausea and vomiting score, shivering score: These score will be recorded at the moment of entering PACU, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, 6 h, 18 h, 24 h, 48 h after surgery.♦ The recovery of gastrointestinal function: Time to first flatus, time to first defecation, time to first liquid drinking and tolerance of a solid diet will be recorded through self-assessment paper.♦ Satisfaction of patients: Satisfaction of patients to anesthesia will be asked at 48 h before surgery.♦ Incidence of postoperative complications: Postoperative hypertension, hypotension, bradycardia, tachycardia, hypoxemia, apnea, perforation, bleeding, aspiration pneumonia will be paid attention to and recorded.♦ QLQ-C30 life quality scale: Patients will be requested to complete this scale before the surgery, at discharge and a month after the surgery.♦ Economic indicators: Postoperative hospital stay and medical costs will be recorded after patients’ discharge.♦ The secondary outcomes are as follows:The observer, under the instruction of statistical professionals, gathers data including the basic information of patients enrolled, primary and second outcomes, incidence of complications, AEs etc. All the original data needed will be recorded accurately and completely in the case report forms (CRF). Any defective cases will be recorded, for example, in which patients forget their time to first flatus, first defecation, first liquid drinking and tolerance of a solid diet. All the period of this study will be monitored by Data Monitoring Committee (DMC), which consists of a doctor responsible for data collection and sorting, a statistician and a scientific research manager. DMC will be independent from the sponsor and competing interests. They will perform unblinding and weigh effectiveness and safety in the middle stage of this clinical study, and make the decision of continuing the trail, adjusting the protocol, or terminating the test, with communication to IRBs. At the end of the research, the distribution information, the original data and results will be presented to the scientific research management committee, who have access to the final trial dataset; they will be kept unknown to the public before the results are published.The primary outcome of this study is the postoperative VAS score. In accordance with the pre-experimental results, there will be no severe postoperative pain until 1 h after the surgery. Therefore, sample size was calculated based on the VAS score at 1 h after the ESD procedure. The mean VAS at 1 h in TEAS group and the sham group in the pre-experiment was 0.86 ± 1.14 and 1.68 ± 1.46, respectively. The PASS 11.0 software was used, with unilateral α = 0.05, β = 0.1 and power = 0.90. A total of 55 effective samples were estimated for each group. Considering of 10% patient loss, we set 60 cases for each group in this study. Eventually, we will involve 120 cases, including 60 patients in the TEAS group and 60 patients in the control group . Our digestive endoscopy center performs 300–400 upper gastrointestinal ESD surgeries, so this trail period is set at 16 months consequently.P < 0.05) will be selected for multivariable logistic regression to explore the association of those with post-ESD VAS ≥ 4. The Hosmer-Lemeshow test will be used to evaluate goodness-of-fit of the model. All P values above are unilateral and P < 0.05 will be considered significant. Subgroup analysis will be conducted in accordance with different procedure types. Intention to treat (ITT) principle will be applied to analyze all data. Because all the data will be collected during hospital stay by a conscientious observer , missing data can be mostly avoided. The mean imputation method will be used if missing data still preserves. The Capital Medical University statistical department will determine detailed analyzing methods for the main efficacy indicators.Statisticians will negotiate with the research team to establish statistical analysis plans, develop databases, and perform statistics with the SPSS statistical analysis system. Statistics analyses include demographic and other baseline characteristics, postoperative pain degree analysis, statistical analysis of recovery time of gastrointestinal function, the incidence of complications and combined treatments, and comprehensive efficacy evaluation. Statisticians will use mean ± standard deviation (SD) to express measurement data that meet the normality test and use t-test to analyze. Non-parametric measurement data will be described as median and interquartile range (IQR), and Wilcoxon signed rank test will be applied. Enumeration data will be expressed as numbers and percentages. Pearson’s chi-squared test and Fisher’s exact test will be the methods applied for these data. Univariate logistic regression analysis will be applied to analyze risk factors which are reported to have possible correlation with VAS ≥ 4 in previous studies. Variables which are considered statistically significant . We try to prove the hypothesis that compare with SA, TEAS may alleviate postoperative pain and enhance gastrointestinal function recovery in patients after ESD.Postoperative pain after ESD is a very common and non-lethal complication, which endoscopists always take for granted. Some previous studies reported an incidence rate of 42.3%-98% of post-ESD pain , 18. JunAccording to previous studies results, female gender, long operation time, lesion location and acid allergy are the potential risk factors of post ESD pain , 18, 19.Currently, no unified conclusion is made on how to perform effective postoperative analgesia on patients with gastric and esophageal ESD surgery. Jung et al. suggested that hypersensitivity to gastric acid had large possibility to fuel the pain after ESD, and the prophylactic treatment of proton pump inhibitor (PPI) was effective in reducing pain . IntraveNowadays, many studies have demonstrated that perioperative acupuncture stimulation can reduce the amount of anesthetic drugs’ consumption , maintaiIn conclusion, this trail is expected to indicate that perioperative TEAS treatment may relieve postoperative pain and promote the recovery of gastrointestinal function for patients undergoing gastric and esophageal ESD procedures. This study aims at seeking a more suitable postoperative analgesia scheme for these patients and solving the current problems of imperfect postoperative analgesia managements and large adverse effects after ESD.The first version was developed on October 10, 2021, and the first participant was recruited on December 1st, 2021; this is the first version, and the version No was V1.0/2021.10.10. The enrollment will be completed on December 30th, 2023. At present, 70 participants have been formally included, and the trial is still ongoing.Additional file 1. Trial registration Information.Additional file 2. SPIRIT 2013 Checklist.