Optimisation of dopaminergic therapy may alleviate fluctuation-related pain in Parkinson’s disease (PD). Opicapone (OPC) is a third-generation, once-daily catechol-O-methyltransferase inhibitor shown to be generally well tolerated and efficacious in reducing OFF-time in two pivotal trials in patients with PD and end-of-dose motor fluctuations. The OpiCapone Effect on motor fluctuations and pAiN (OCEAN) trial aims to investigate the efficacy of OPC 50 mg in PD patients with end-of-dose motor fluctuations and associated pain, when administered as adjunctive therapy to existing treatment with levodopa/dopa decarboxylase inhibitor (DDCi).OCEAN is a Phase IV, international, multicentre, randomised, double-blind, placebo-controlled, parallel-group, interventional trial in PD patients with end-of-dose motor fluctuations and associated pain. It consists of a 1-week screening period, 24-week double-blind treatment period and 2-week follow-up period. Eligible patients will be randomised 1:1 to OPC 50 mg or placebo once daily while continuing current treatment with levodopa/DDCi and other chronic, stable anti-PD and/or analgesic treatments. The primary efficacy endpoint is change from baseline in Domain 3 (fluctuation-related pain) of the King’s Parkinson’s disease Pain Scale (KPPS). The key secondary efficacy endpoint is change from baseline in Domain B (anxiety) of the Movement Disorder Society-sponsored Non-Motor rating Scale (MDS-NMS). Additional secondary efficacy assessments include other domains and total scores of the KPPS and MDS-NMS, the Parkinson’s Disease Questionnaire (PDQ-8), the MDS-sponsored Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts III and IV, Clinical and Patient’s Global Impressions of Change, and change in functional status via Hauser’s diary. Safety assessments include the incidence of treatment-emergent adverse events. The study will be conducted in approximately 140 patients from 50 clinical sites in Germany, Italy, Portugal, Spain and the United Kingdom. Recruitment started in February 2021 and the last patient is expected to complete the study by late 2022.The OCEAN trial will help determine whether the use of adjunctive OPC 50 mg treatment can improve fluctuation-associated pain in PD patients with end-of-dose motor fluctuations. The robust design of OCEAN will address the current lack of reliable evidence for dopaminergic-based therapy in the treatment of PD-associated pain.2020–001175-32; registered on 2020-08-07.EudraCT number  Pax corporis’, by Ferenc Pápai Páriz); however, it was only in 1817 that James Parkinson medically described the motor symptoms of the disease in such detail that the condition would subsequently be named after him [Although fragmented accounts of Parkinsonism date back to 2500 BC, initial descriptions of its cardinal motor signs were much more recent  is variable and not necessarily linear, many NMS – specifically pain – can undergo fluctuations based on ON and OFF states during long-term treatment with levodopa , 5. NMS Pain is one of the most frequent and burdensome NMS in PD, being a significant comorbidity in up to 85% of PD patients, and may precede motor symptoms of the disease –16. The Pain in PD is also associated with motor fluctuations , 26. TheLevodopa is still the most effective symptomatic treatment for PD . HoweverOpicapone (OPC) is a third-generation, once-daily COMTi , 45, 46,Given the probable dopamine-related pathophysiology of motor fluctuation-associated pain  and the OCEAN is a Phase IV, international, multicentre, randomised, double-blind, placebo (PLC)-controlled, parallel-group, interventional trial in PD patients with end-of-dose motor fluctuations and associated pain . It consists of a 1-week screening period, 24-week double-blind treatment period and 2-week follow-up period . At V2b, after eligibility for entry into the treatment phase is confirmed, site staff will contact the IWRS to obtain the appropriate medication number. Randomisation will follow a 1:1 allocation rate (OPC 50 mg or PLC) and the randomisation list will be produced by the contract research organisation  using the Statistical Analysis System (SAS) for Windows . The original list will be kept at the contract research organisation. Each patient’s investigational product will be determined by their randomisation number and corresponding medication number. OPC 50 mg and PLC capsules will be identical in size, colour, taste and appearance, and the packaging and labelling will not allow distinction between treatments. No person involved in conducting the study will have access to the randomisation code before the blind is officially broken. Unblinding will not occur unless there is an actual emergency and knowledge of the patient’s allocated treatment arm affects their treatment, in which case the individual treatment assignment for each patient will be available to the principal investigator/authorised delegate and responsible medical monitor via the IWRS. Patients with suspected unexpected serious adverse reactions (SUSARs) will be unblinded for regulatory reporting by the contract research organisation’s safety manager. Other study personnel and the investigators will receive blind information on the SUSAR until the study has been unblinded. The medication will be supplied by the sponsor  and the investigator/institution and/or a pharmacist or other appropriate individual (designated by the investigator/institution) will maintain records of delivery, inventory usage, and return any unused study medications. The investigator or an authorised delegate will be responsible for dispensing medication to the patients according to the dosage scheme and IWRS. At each study visit, site staff will dispense the appropriate amount of investigational product and rescue medication for each patient and for each treatment interval plus one extra week per 4 treatment weeks. At each visit, patients must bring back the study medication  and accountability will be performed and documented.The study will be conducted in accordance with: the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Patients adopted by the General Assembly of the World Medical Association (2013); the applicable regulatory requirements of the participating countries; the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Harmonised Guideline – integrated addendum to ICH E6(R1) Guideline for Good Clinical Practice E6(R2); and with the European Commission Directives 2001/20/EC and 2005/28/EC, and EU Regulation No. 536/2014. The protocol will be submitted to national Independent Ethics Committee(s) and Competent Authorities and unconditional approval/favourable opinion must be obtained before the start of the study. All patients must provide written informed consent in order to participate in the study.Data processing will be conducted by the contract research organisation. This will include, but is not limited to, producing the patient diary and electronic case report form, and setting up a relevant database and data transfer mechanisms, along with appropriate validation of data and resolution of queries. Clinical data will be collected in electronic form using an electronic data capture system. All clinical data will be recorded, processed, handled and stored without disclosing personal information of the patients so that the data can be accurately reported, interpreted and verified while the confidentiality of records and the personal data of the patients remain protected, in accordance with the applicable rules on personal data protection.The study will be conducted in approximately 50 clinical sites in Germany, Italy, Portugal, Spain and the United Kingdom. Other countries and additional sites may be added, if required. Inclusion and exclusion criteria are outlined in Table An overview of study assessments is presented in Table The primary efficacy endpoint is change from baseline in Domain 3 (fluctuation-related pain) of the KPPS. The KPPS evaluates the burden and characterises various phenotypes of pain in PD. It comprises seven domains including a total of 14 items. Each item is scored by severity (0–3) multiplied by frequency (0–4), resulting in subscores of 0–12. The total KPPS score (0–168) represents the symptomatic burden by pain .The key secondary efficacy endpoint is change from baseline in Domain B (anxiety) of the Movement Disorder Society-sponsored Non-Motor rating Scale (MDS-NMS). The MDS-NMS comprises 13 domains covering a range of key PD- and treatment-related NMS, and a subscale for NMF that assesses changes in NMS in relation to timing of anti-PD medications across eight domains , 55. AddThe MDS-UPDRS is a revision of the UPDRS originally developed in the 1980s, and evaluates various aspects of PD; it consists of four parts : Parts ISafety assessments include the incidence of treatment-emergent AEs (TEAEs), and changes from baseline in vital signs, physical and neurological examinations and routine laboratory parameters Table ; Fig. 2.For the primary efficacy endpoint (change from baseline in Domain 3 of KPPS), a difference to PLC of 3.0 is regarded as clinically meaningful. From a former study , a standEfficacy assessments will be analysed for the Full Analysis Set, defined as all patients who are randomised and who have at least one measurement of the primary efficacy assessment. For sensitivity purposes, efficacy assessments will additionally be analysed for the Per-Protocol Set, defined as all patients included in the Full Analysis Set who have no major protocol deviations that could influence the primary efficacy assessment. The primary efficacy endpoint will be analysed using analysis of covariance (ANCOVA), with treatment as a fixed factor and baseline KPPS as a covariate, to demonstrate superiority of OPC 50 mg against PLC. Secondary efficacy endpoints will be analysed in an exploratory manner by treatment arm using appropriate parametric and non-parametric statistical methods. Descriptive statistics, including 95% confidence intervals, will be presented per treatment arm.Safety assessments will be analysed for the Safety Set, defined as all patients who take at least one dose of investigational product. TEAEs will be summarised in terms of the number and percentages of patients with TEAEs. Vital signs and laboratory parameters will be summarised using summary statistics of absolute values and changes from baseline. Summary statistics and shift tables will be presented for physical and neurological examinations. Demographic and baseline characteristics will be presented using descriptive statistics. The statistical analysis plan will be carried out by biostatisticians from the contract research organisation.The first patient was enrolled in February 2021 in the UK. The recruitment window is now open and the last patient is expected to complete the study by late 2022. Timelines might be impacted by recurring COVID-19-related lockdowns impairing the access of patients to healthcare facilities.2 receptors [Pain has a major impact on the quality of life of patients with PD , 58–60 aeceptors , pain aseceptors , 22, 29.post-hoc analysis of two previous trials and must therefore be interpreted with caution.Management of pain, among many other non-motor aspects of PD, remains a key unmet need  and therThe design of the OCEAN study will address the current lack of reliable evidence for levodopa-based therapy in the treatment of PD-associated pain. OCEAN features recent validated PD pain- and non-motor-specific scales (such as the KPPS and the MDS-NMS), which might help to record dimensions of PD-associated pain that have not been previously studied. For instance, this study may allow the detection of potential associations between pain and other NMS, such as depression, anxiety and insomnia, and dysautonomic symptoms. The concomitant use of ON/OFF diaries with these scales may also allow a deeper understanding of pain and other NMS, such as the key secondary endpoint anxiety (as assessed by change from baseline in Domain B of the MDS-NMS), during both the OFF and ON states. Anxiety problems, including OFF-period anxiety, are highly prevalent in PD and greatly impact quality of life , 64. AltIn summary, the OCEAN study will provide valuable information on whether the use of adjunctive OPC 50 mg treatment can improve fluctuation-associated pain in PD patients with end-of-dose motor fluctuations. The data will address the current lack of Level 1 evidence for the recommendation of strategies to manage aspects of pain in PD.


Allergen immunotherapy (AIT) can induce immune tolerance to allergens by activating multiple mechanisms, including promoting IgG4 synthesis and blunting IgE production. However, the longitudinal data of sIgE and sIgG4 to allergen components during AIT are limited.We sought to investigate the persistence and evolution of sIgE and sIgG4 against house dust mite (HDM) components during AIT and explore their correlation with clinical responses.Derp 1, Derf 1, Derp 2, Derf 2, Derp 7, Derp 10, Derp 21 and Derp 23) assay at baseline, Month 6 and Month 18 of AIT. Combined symptom and medication scores (CSMS) were obtained accordingly.Sixty allergic rhinitis (AR) with/without asthma patients receiving AIT for HDM were enrolled in AIT group. Thirty AR patients without receiving AIT served as control group. Blood samples were collected for sIgE, sIgG4 to HDM components , sIgE to HDM components didn’t see differences at baseline and at Month 18 .The numbers of positive HDM component sIgE and sIgG4 increased from 4.5 to 5 and 0 to 1.5 respectively (both p<0.05). However, the changes of sIgE, sIgG4, sIgE/sIgG4 ratio and the numbers of positive HDM components had no correlations with the improvement of CSMS after AIT . For the control group, the sIgE and sIgG4 did not change significantly during the observational period .In the AIT group, sIgG4 to the HDM components of AIT can induce the production of sIgG4 to HDM components. However, the increased sIgG4 levels of HDM component do not correlate with the corresponding sIgE levels at baseline or with AIT response. sIgG4 to HDM components do not qualify as a biomarker to evaluate the efficacy of AIT. For respiratory allergies, allergen immunotherapy (AIT) is the only etiological treatment option which can provide long-term relief of symptoms even after treatment cessation . The proin vitro assays (Derp1 and Derp2 may be a risk factor for developing asthma in HDM-AR patients (Component-resolved diagnosis (CRD)is a method recently developed to detect IgE antibodies with the allergen components. CRD makes it possible to obtain the individual sensitization profile to a certain allergen , 8. It ao assays . Take hoo assays . So far,o assays . The seno assays . For exapatients .Der p 1 and Der p 2 but not all components  were diagnosed with HDM-induced AR with/without asthma according to Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines and Global Initiative for Asthma (GINA) guidelines , 15; (2)Four AR symptoms  were measured on a scale from 0 to 3 . The average value of the four symptom scores (ranging from 0 to 3) was the final symptom score. All subjects received medications according to the ARIA and/or GINA guidelines, including nasal corticosteroids and antihistamines. The medication score was defined as 0 = “no rescue medication taken”; 1 = “use of antihistamines ”; 2 = “use of nasal corticosteroids”; and 3 = “use of oral corticosteroids”. The highest score was recorded for the medication score if more than 1 class of rescue medication was used on a particular day. The medication score ranged from 0 to 3. The combined symptom and medication score (CSMS) was the sum of symptom scores and medication scores (ranging from 0 to 6). CSMS was obtained at baseline, Month 6 and Month 18 of AIT .All these patients receiving subcutaneous immunotherapy followed a conventional schedule with a commercial product of ALK  or NHD  according to the manufacturer’s instructions.Derp 1, Derf 1, Derp 2, Derf 2, Derp 7, Derp 10, Derp 21 and Derp 23) assay at three time points  for the AIT group, two time points (baseline and Month 18) for the control group. The sIgE against Dermatophagoides pteronyssinus (Der p) and Dermatophagoides farinae (Der f) were measured by ImmunoCAP-250 system (Thermo Fisher Scientific), sIgE level over 0.35 kUA/L was defined as positive. sIgE and sIgG4 of HDM components  were measured by HDM components sIgE and sIgG4 test kit . The recombinant HDM components  were precoated on the chip. After serum was incubated on the chip for 1-hour, anti-human IgE/IgG4 antibodies (conjunct by biotin) and alkaline phosphatase-streptavidin were added consecutively. The concentrations of IgE/IgG4 were calculated by a series of IgE/IgG4 protein standardizations. The positive cut-off value of sIgG4 was set by 95% percentile of upper limit of 210 healthy non allergic donors, sIgG4 to HDM components above 156 UA/mL was defined as positive. SIgE to HDM components level above 0.35 IU/mL was defined as positive.Blood samples were collected for sIgE, sIgG4 to HDM components  and then blocked with bovine serum albumin at 1% in phosphate-buffered saline solution plus 0.05% Tween-20. Then, 100µlof diluted serum was incubated in the plates 3 times (1:1) for 3 hours at 37.0°C. The sIgE and sIgG4 of HDM components of the supernatant and the diluted serum (1:1) were measured by ZhedaDixun test kit as previously described.6 in 100µl FACS staining buffer and were stained with anti-human CD3, CD4, CD279 (PD-1), CD183 (CXCR3), CD185 (CXCR5), CD294 (CRTH2), CD25 and Foxp3 antibodies . Stained cells were acquired with Cytek Aurora flow cytometer  and the data were analyzed with Flowjo software .PBMCs of patients at baseline and after 18-month AIT were isolated and stored in liquid nitrogen. Thawed PBMCs were incubated with 40µg/mL HDM allergen for 5 days, then the harvested cells were prepared at a concentration of 1×10p<0.05 was considered statistically significant. All statistical analyses were performed with GraphPad Prism 9.0 .Descriptive parameters, such as means and Standard Error of Mean (Mean ± SEM) for normally distributed continuous data, frequencies, and percentages for categorical data, were calculated. The abnormal distribution data were expressed as median and 25% to 75% interquartile ranges. T-test and non-parametric Wilcoxon paired test were used for comparisons of data in normal and non-normal distributions, respectively. The Mann–Whitney U test was used to compare numerical data between groups, and the Spearman rank test was used to assess correlations. p<0.05). The mean CSMS score was 2.9 ± 0.3, 3.2 ± 0.2 and 4.1 ± 0.5 respectively at baseline. There were no significant differences in demographic characteristics in the control, NHD and ALK groups . The sIgE and sIgG4 levels of HDM components at baseline were also showed in Derp 1, Derf 1, Derp 2 and Derf 2, Derp 7, Derp 10, Derp 21 and Derp 23 respectively. Only 36.7% of patients had positive IgG4 (>156 UA/mL) to HDM components at baseline.A total of 90 AR patients  were included. The mean age has no statistical difference within the three groups . Twenty-one patients had history of asthma, only two were in the control group (K groups Table 1.p>0.05). In the AIT group, the pattern of sIgE against HDM components didn’t show obvious changes during AIT; however, the sIgG4 against Der p 1, Der f 1, Der p 2, Der f 2, Der p 7 and Der p 21 significantly increased in a time-dependent manner during AIT (p<0.05)  Figure 2p>0.05). However, during the course of AIT, the sIgEs against Der f 2 and Derp21 were statistically elevated during the up-dosing period (0M-6M) and decreased from 6M to 18M in the ALK group. The sIgG4 against Der p 1, Der f 1, Der p 2, Der f 2 and Der p 21 showed a significant increase after 18 months of AIT in the NHD group and Der p 1, Der f 1, Der p 2, Der f 2 and Der p 7 in the ALK group. The sIgG4 against Der p 1, Der f 2, Der p 21 in the NHD group and Der f 2 in the ALK group already increased only after 6 months of AIT.The trend lines of the allergenic HDM components leading to production of sIgE and sIgG4 were shown in p<0.001). Meanwhile, the number of positive sIgE against HDM components also increased after AIT in the two groups, which showed a similar pattern as sIgG4 (both p<0.05)  Table 2.Der p1 and Der f 1 showed mild correlation with sIgG4 of Der f 2. sIgE of Der f 2 correlated with sIgG4 of major HDM components  . In the NHD group and ALK group, the sIgE of major HDM components at baseline had weak correlations with sIgG4 levels of major HDM component and no correlation with sIgG4 levels of Der p 7, Der p 10, Der p 21 and Der f 23. Meanwhile, sIgE at baseline of Der p 7, Der p 10, Der p 21 and Der f 23 had no correlation with all the sIgG4 of HDM components after AIT in most cases.IgG4 can competitively block the binding of IgE to antigen. Our study tried to look into the correlation of sIgE level at the baseline and sIgG4 levels at Month 18 of control patients and AIT patients. What interested us was the HDM components sIgG4 after Month 18 showed mild or no correlations to their corresponding component of sIgE at baseline in all the three groups Figure 5Der p 10 sIgE in our study with the 9 selected patients to analyze.For 9 randomly selected AIT patients, the IgG4 antibody was removed from the serum by anti-IgG4 antibody through ELISA. The positive sIgE levels of the eight HDM components before and after sIgG4 removal were shown in +CXCR3+), allergen-stimulated Th2(CD4+CRTH2+), allergen-stimulated Tfh (CD4+CXCR5+PD-1+) and allergen-stimulated Treg (CD4+CD25+Foxp3+) had no significant changes after AIT. However, the changes of Tfh(ratio=baseline/after AIT) were correlated with the change of sIgE HDM components  and sIgG4 Der f 23. Meanwhile, the change of Treg correlated with the change of sIgE HDM components  and sIgG4   decreased while metacluster 2(CD3+ CD4+ CD25+ PD-1+) increased after AIT  Figure 7p<0.05) (p>0.05) (p>0.05) (data not shown).Both the NHD group and the ALK group showed a significant reduction in symptom and medication score (CSMS) at Month 6 and Month 18 of AIT compared to baseline  Figure 8In this study, we investigated the profile of sIgE and sIgG4 against HDM components at different time-points of AIT under real-life conditions and their correlation with AIT responses. Here we presented the data of AIT with two commercially standardized HDM extracts. We found that the levels of sIgE saw an early increase at up-dosing period and a late decrease at maintenance period while the levels of sIgG4 showed a continuous increase during 18 months of AIT. We also found the numbers of positive sIgE and sIgG4 to HDM components increased after AIT. However, the levels of sIgE and sIgG4 against HDM component didn’t show correlations with AIT responses, which implies the IgG4 against allergen components may not qualify as a biomarker to evaluate the response of AIT.Der f 1, Der p 1, Der p 2 and Der f2. Meanwhile, less than 33.3% of these patients were sensitized to Der p 7, Der p 10, Der p 21, which was in accord with our expectation as these 3 components had been reported as minor HDM allergens in many studies. Der p 23 is a recently identified HDM major allergen which was supposed to cause asthmatic disease with relatively high sensitization rates (ranging from 70% to 87%) in European countries  after AIT. However, the changes of Tfh were correlated with sIgE and Treg correlated with sIgG4. Our results suggested that the switch of IgE to IgG4 after AIT may be due to the conversion of the subsets of CD4+T cells. In the FLOWSOM analysis, the cluster cells (CD3+CD4+CXCR5+) decreased, which could induce B-cell activation and share functional properties with Tfh cells  began to express PD-1 after AIT. The effect of this cluster cell (CD3+ CD4+ CD25+PD-1+) was not reported in AIT before. However, it was identified in tumor microenvironment as PD-L1hi Tregs to predict the response to PD-1/PD-L1 blockade immunotherapy . We found the post-treatment sIgE and sIgG4 patterns were slightly different in the two AIT groups, but we couldn’t figure out if it was caused by the different allergen components of the two HDM extracts or by the imbalance of IgE pattern at baseline.There were some limitations in our study. Firstly, the study population in each group was relatively small. Secondly, the observational period was relatively short (18 months) whereas AIT was suggested to last for 3 to 5 years according to the current guidelines. In addition, our study was based on the patients who finished 18-month AIT. Some patients dropped out due to less efficacy and their data were not included in the analysis, which possible slightly biased interpretation of data. Thirdly, the pattern of IgE reactivity at baseline of the control group and the two AIT groups were different. However, it may not be really important to our study, as the role of control group was not to compare with the AIT groups directly, but to investigate the changes of IgE and IgG4 patterns over a relatively long term (18 months) of natural HDM exposure. With the control group, we could ensure the data observed in the AIT groups were attributed to the treatment but not to HDM exposure. Finally, the aim of our study was to investigate the changes of IgE and IgG4 profiles during AIT, although the direct comparison between the two AIT groups may not be really important in this study, it would be interesting to know if different allergen extracts could induce similar or different antibody responses. However, the sIgE against In summary, our study revealed longitudinal evolution of sIgE and sIgG4 against HDM components during AIT shown in an early increase and a late decrease of IgE level and a continuous increase of sIgG4 level. However, the pretreated IgE sensitization patterns couldn’t determine the molecular profile of the IgG4 responses during AIT. The post-treated sIgE and sIgG4 profiles had no correlations with AIT efficacy. Future studies combining antibodies functional binding, allergen epitope sensitization and clinical manifestations may help to elucidate the mechanism of AIT.TJ-IRB20210761The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Medical ethics committee of Tongji Hospital, Tongji Medical College of Huazhong University of science and technology. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.RZ and BS were responsible for the work as a whole. LY analyzed the HDM components data in the study and wrote the first draft of the manuscript. YY, WL, YW, and DM were responsible for CSMS data. QX and XL were responsible for data analysis. WZ and QJ contributed to IgE test by ImmunoCAP. All co-authors have contributed to the interpretation of the data and provided advice and approval of the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


BackgroundLaparoscopic cholecystectomy is widely performed, and postoperative pain is an important factor in patient morbidity during recovery. Various modalities for postoperative pain relief have been proposed, with varying levels of success such as intravenous or intramuscular non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, infiltration at the incision site with local anesthetics, intraperitoneal infiltration of local anesthetics, intraperitoneal infiltration of local anesthetics with adjuvants, regional anesthesia techniques such as epidurals and nerve blocks. The study was aimed to evaluate the efficacy of intraperitoneal instillation of bupivacaine and normal saline on postoperative analgesia, postoperative nausea, and vomiting after laparoscopic cholecystectomy.MethodsThis prospective, controlled, and randomized study included 60 American Society of Anesthesiologists (ASA) I and ASA II patients, aged 18-50 years, who were scheduled for laparoscopic cholecystectomy under general anesthesia. The patients were classified randomly into two groups with an equal number of participants: Group B received intraperitoneal instillation of 30 ml of plain bupivacaine 0.5% and Group N received 30 ml of normal saline. Postoperative pain was recorded using the visual analog scale (VAS) for 24 hours after surgery. Postoperative shoulder pain, nausea, vomiting, and the time taken to request rescue analgesia were noted.ResultsPatients receiving intraperitoneal bupivacaine showed a significant reduction in postoperative pain for the first six hours postoperatively (P = 0.04); moreover, the time taken to request rescue analgesia requirement was prolonged (P = 0.04). Side effects, such as nausea and vomiting, were similar between the two groups  while shoulder pain was significantly lower in the bupivacaine group (P = 0.04).ConclusionBupivacaine is effective in reducing postoperative pain, and it prolongs the requirement time for rescue analgesia. It also reduces the incidence of shoulder pain but does not decrease postoperative nausea and vomiting. Laparoscopic cholecystectomy is widely performed, and it has replaced open cholecystectomy as the gold standard for cholelithiasis. Laparoscopic surgeries are favored over open surgeries because they have a number of advantages such as reduced postoperative pain and analgesic requirement, improved postoperative respiratory function, rapid return of gastrointestinal function, a reduced stress response to surgery and recovery time, less postoperative wound infection, and improved cosmetic appearance -3.Postoperative pain is an important factor contributing to patient morbidity during recovery. After laparoscopic cholecystectomy, pain can arise from the incision site (somatic pain), visceral structures  , and shoVarious modalities are used for postoperative pain relief, including intravenous or intramuscular NSAIDs  and opioThe present study was conducted to evaluate the effects of the intraperitoneal instillation of bupivacaine and normal saline on postoperative analgesia and postoperative nausea and vomiting (PONV) in patients undergoing laparoscopic cholecystectomy.This randomized, prospective, double-blind study was conducted in ACS Medical College Hospital from June 2020 to December 2020, after obtaining approval from the Institutional Ethics Committee, and written informed consent was obtained before surgery from all the patients participating in the study.The study population consisted of 60 male and female patients, ranging in age from 18 to 50 years, with either an American Society of Anesthesiologists (ASA) I or ASA II physical classification status that was scheduled for elective laparoscopic cholecystectomy under general anesthesia. Exclusion criteria were patient refusal, pregnant or lactating patients, a body mass index (BMI) of > 40, allergy to local anesthetics, patients with cardiac, pulmonary, neurological, and renal diseases, any patient who needed conversion to open cholecystectomy, previous history of abdominal surgeries, and duration of surgery of > two hours.The patients were randomized into two groups of 30 patients each using sequentially numbered envelopes. To maintain the double-blind nature of the study, the randomization and preparation of the drug for injection were done by an anesthesiologist not involved in the study. Group N received 30 ml of normal saline and Group B received 30 ml of 0.5% plain bupivacaine. The postoperative follow-up of the study participants was done by the co-author who was blind to the patient group assignment.All the patients fasted overnight, and the preoperatively enrolled patients received instructions about the visual rating scale employed in this study to indicate their pain. On arrival to the operating room, an 18-gauge intravenous (IV) cannula was secured and IV fluids at 2 ml/kg were started. The Association of Anaesthetists of Great Britain and Ireland (AAGBI) standards for monitoring started and baseline vital parameters were noted.2 (EtCO2) between 35 and 40 mmHg. No other intraoperative analgesic supplementation was used. CO2 was used to institute pneumoperitoneum, and the intra-abdominal pressure was maintained between 12 and 14 mmHg. The patients were placed in a 15-30-degree reverse Trendelenburg position with a left lateral tilt.General anesthesia with endotracheal intubation was administered in all patients using propofol 2 mg/kg, fentanyl 2 ug/kg, and vecuronium 0.1 mg/kg after pre-oxygenation with 100% oxygen for three minutes. The airway was secured with an appropriately sized, cuffed endotracheal tube. Anesthesia was maintained with 50% oxygen and 50% air with 1% isoflurane and intermittent doses of muscle relaxant. Minute ventilation was adjusted to maintain End-tidal COAt the end of the surgery, the study drugs, as per group allocation, were instilled in equal amounts into the sub-diaphragmatic space and intraperitoneally under direct vision, and the patients were placed in the Trendelenburg position. The pneumoperitoneum was removed carefully by manual compression and suction of the abdomen at the end of the procedure through the trocar. The patients were reversed with intravenous neostigmine and glycopyrrolate and extubated. All patients were transferred to the post-anesthesia care unit following extubation.The intensity of postoperative pain was recorded for all patients using the visual analog scale (VAS) score at 0, 2, 4, 6, 12, and 24 hours, with 0 referring to the time the patient was transferred to recovery. In patients that complained of moderate to severe pain, 100 mg of tramadol was administered IV as a rescue analgesia treatment, and the time interval to the first request for rescue analgesia was noted. Adverse effects of nausea, vomiting, and shoulder pain over the course of 24 hours were noted. All postoperative findings were compared between the two study groups.Data were collected, tabulated, and coded, and then analyzed using repeated-measures analysis of variance (ANOVA), the student's t-test, and the paired t-test. The Statistical Package of the Social Sciences (SPSS) version 15 for Windows  was employed for the data analysis. A difference with a p level of < 0.05 was considered statistically significant.All the patients in Group B and Group N were comparable in terms of age, weight, sex, and the duration of surgery Table .The VAS score was assessed at zero hours (the time when the patient was transferred to recovery) and at two, four, six, 12, and 24 hours. The mean VAS score in Group B was 1.56 at zero hours, 1.99 at two hours, 2.11 at four hours, 2.45 at six hours, 3.36 at 12 hours, and 3.53 at 24 hours. The mean VAS score in Group N was 3.46 at zero hours, 3.83 at two hours, 3.90 at four hours, 4.22 at six hours, 4.32 at 12 hours, and 4.38 at 24 hours. The VAS score was statistically significantly lower in Group B at zero, two, four, and six hours in comparison to Group N; the P-value was 0.05 (0 hours), 0.04 (2 hours), 0.04 (4 hours), and 0.04 (6 hours). The VAS score between the two groups did not show any significant difference at 12 hours (P = 0.1) and 24 hours (P = 0.7)  . Shoulder pain was seen in 17 patients in Group N and seven patients in Group B, which was statistically significant (P = 0.04) Table .Laparoscopic cholecystectomy is a widely performed, common, elective procedure. Postoperative pain is comparatively less after laparoscopic cholecystectomy than after an open cholecystectomy, but it still remains a significant cause for morbidity . Patient2, resulting in distension of the abdominal wall. This type of pain is dull, more diffuse than parietal pain, and difficult to locate. The prolonged elevation of the diaphragm and residual gas from pneumoperitoneum leads to referred shoulder tip pain. Normal saline infiltration reduces visceral pain and referred pain by causing dilution of the inflammatory markers, replacing the gas above the liver, and reducing the space between the liver and the diaphragm [Patients undergoing laparoscopic cholecystectomy suffer considerable pain on the day of surgery, frequently requiring opioid analgesia. After laparoscopic cholecystectomy, several types of pain can arise. Parietal pain is due to the placement of trocars through the abdominal wall. It is superficial and can be located by the patient. Visceral pain is due to intraperitoneal dissection and insufflation of COiaphragm . BupivacThe demographic data were similar in both study groups. The overall duration of surgery was similar for both groups. In our study, the VAS score was lower in Group B  in comparison to Group N . This finding was similar to the results reported in Devalkar and Salgaonkar  and SumaThere are a few studies in which the administration of a local anesthetic did not show any efficacy. These failures could be due to the use of a lower drug dose, a lower concentration, or because the entire dose was infiltrated under the right hemidiaphragm ,18-19.In our study, postoperative shoulder tip pain was lower in Group B than Group N. Putta et al. also showed that the incidence of shoulder pain was significantly reduced in groups receiving bupivacaine in comparison to those receiving normal saline and that the timing of the bupivacaine infiltration  was not significant .In our study, the mean time taken for the first dose of analgesic was 182 minutes in Group B and 70 minutes in Group N. Similarly, the study by Sulekha showed that the dosing of rescue analgesia was more frequent and the highest in patients that received normal saline in comparison to those that received bupivacaine . A studyNo statistically significant difference was found in the incidence of PONV in Group B  and Group N . No side effects or toxicity were recorded due to bupivacaine use. Hazinedarogle et al. reported the same results . GoldsteIn our study, we found that bupivacaine reduces postoperative pain and prolongs the requirement time of rescue analgesia. It also reduces the incidence of shoulder pain after laparoscopy. We conclude that the intraperitoneal and subdiaphragmatic instillation of 0.5% bupivacaine is a safe and effective method for providing postoperative analgesia without significant side effects.


The rural area patients presented higher levels of acceptance and pain and lesser levels of physical and mental fatigue compared to the urban area. The moderation analysis add that, only in patients from the rural area, the variables of physical symptoms  were significantly and negatively associated with acceptance. This study addresses for the first time the role of the place of residence in suffering from fibromyalgia, suggesting that the rural or urban environment plays a relevant role in the severity and/or management of symptoms in fibromyalgia women. Limitations and practical implications are also discussed.The present study aims to explore whether the symptoms associated with fibromyalgia are contextually influenced by the area of residence . Furthermore, it is analyzed whether the effect of the acceptance of the disease on the emotional, cognitive and physical symptoms is moderated by the patients’ place of residence. Using a cross-sectional design, a total of 234 women with fibromyalgia  were surveyed, of which 55.13% resided in rural areas and 44.87% in urban areas. Self-reported questionnaires were used to assess pain severity, anxiety and depression, functional limitation, physical and mental fatigue and acceptance of the disease. The results show significant differences in acceptance ( Fibromyalgia (FM) is considered a chronic disease characterized not only by chronic widespread pain but also by other symptoms such as fatigue, sleep problems, anxiety, or depression. Fibromyalgia causes a negative impact on the quality of life of patients  and has From the recognition of FM as a disease to the present, the scientific community has tried to identify which biopsychosocial factors are involved in its appearance, maintenance and severity . It is kThe literature also suggests that the relationship established between psychological factors and health outcomes is not always linear, but depends, to a large extent, on the context . As suggGiven the increasing prevalence of FM, both in rural (between 0.1 and 5.2%) and urban (between 0.7 and 11.4%) populations , the firThe study design was a cross-sectional cohort. The Ethics Committee of the Rey Juan Carlos University approved the study protocol and evaluation procedures . In this study, the Strengthening of the Notification of Observational Studies in Epidemiology (STROBE) guidelines for cross-sectional studies was followed and applied .Two hundred thirty-four women with FM were recruited with a mean age of 56.91 years (SD = 8.94). Of these, 129 participants (55.13%) reside in rural areas and 105 (44.87%) reside in urban areas. Six percent of the women had completed higher education studies, 29% completed secondary studies and 65% primary studies. Fifty-three percent of the women were married or in a stable relationship, 11% were single, and 36% of them were divorced or widowed. The vast majority of the participants were housewives (78%). Participants had a diagnosis of FM for an average of 12.14 years . The mean intensity of perceived pain was 7.28 .Only female adults were included in this study . The eligibility criteria to participate in the present study included having a diagnosis of FM according to the American College of Rheumatology (ACR) criteria , 2010, bA convenience sample was selected by contacting several patient associations from different Spanish regions during the years 2018 and 2019. In total, 268 participants agreed to participate in the study and met our initial inclusion criteria. Finally, effective responses were obtained from 234 patients . The initial sample size was calculated based on recommendations for similar studies . The 234To assess pain intensity, the mean score of the four pain intensity items from the Brief Pain Inventory (BPI) was used : maximumThe Spanish version of the Hospital Anxiety and Depression Scale (HADS) was used to measure the presence and severity of symptoms of anxiety and depression . The HADThe dimension of “physical function or functional limitation” of the Spanish adaptation of the Revised Fibromyalgia Impact Questionnaire (FIQ-R) was used for this study . The FIQFor this study, the dimensions of physical and mental fatigue were selected from the Spanish version of the Multidimensional Fatigue Inventory (MFI) . This quFor this study, the subscale of “commitment to activity” of the Spanish version of the Chronic Pain Acceptance Questionnaire (CPAQ) was selected . The CPAad hoc questionnaire was used to evaluate age, place of residence, educational level, employment status, and marital status. Regarding clinical variables, duration of FM was recorded.An t-test and the Chi-square test for continuous and categorical variables, respectively. For the analysis of differences between the rural and urban groups in the symptoms of the disease controlling for age, a one-way multivariate analysis of covariance (MANCOVA) was conducted. Effect size differences were assessed using ηp2   .Post hoc analyses were then computed when a significant moderation was found. This was done to obtain the conditional effects of the independent variables on outcomes at different levels of the moderator and to graphically represent the moderation findings.Next, a series of multivariate regressions were computed with model 1 of the PROCESS macro . Bootstrt = 4.20, p < 0.001), educational level , employment status  and marital status . Specifically, patients from rural areas are older and have a lower educational level; furthermore, they are mostly housewives and are married.F = 5.13, p = 0.007, ηp2 = 0.05), obtaining the rural area  higher levels of acceptance with respect to the urban area .The results show significant differences in acceptance regarding the area of residence (p < 0.001) and lower in physical fatigue (p = 0.008) and mental fatigue (p = 0.008). Pain has the highest effect size (medium effect). No statistically significant differences were observed in the rest of the symptoms considered.As shown in p = 0.008), depression (p = 0.018) and mental fatigue (p < 0.001). No direct effects of acceptance were observed on pain, functional limitation and physical fatigue . That is, once the sociodemographic variables have been controlled, acceptance is negatively related to anxiety, depression, and mental fatigue, regardless of the place of residence .p = 0.016), acceptance and functional limitation (p = 0.029), as well as between acceptance and physical fatigue (p = 0.042). The relationship between acceptance and anxiety, depression and mental fatigue was not moderated by area of residence . That is, once the sociodemographic variables have been controlled, the relationship between acceptance and pain, functional limitation, and physical fatigue depends on the area of residence.Regarding the moderation analyzes, the results revealed that the residence area moderated the relationship between acceptance and pain (p’s < 0.01).The evaluated models predicted a significant variance of 9% for pain, 5% for functional limitation and 14% for physical fatigue  on health symptoms and disease acceptance in FM patients. Specifically, it was found that patients residing in rural settings reported significantly higher levels of pain and lower levels of physical and mental fatigue than those residing in urban areas. To our knowledge, similar studies have not been carried out in FM patients, which makes it difficult to compare results. Despite this, previous literature in the general population also indicates that women in rural areas have higher pain scores than those in urban areas . It coulInterestingly, our findings did not reveal significant differences in anxiety, depression, and functional limitation between the rural/urban groups. Previous literature in clinical and non-clinical populations is not consistent with the results obtained in this regard. Specifically, studies in patients with multiple chronic conditions report that rural subjects have more symptoms of anxiety and depression . In the Regarding acceptance, the results show significant differences with respect to the area of residence. Specifically, patients from rural areas obtain higher scores in this variable compared to those from urban areas. Previous literature on the matter in patients with FM is non-existent. Studies carried out on samples with other diseases  did not find significant differences on acceptance according to the place of residence . It is iRegression analyzes revealed that the role of place of residence  in the effect of acceptance on emotional, cognitive, and physical symptoms differed by symptom. It is described that regardless of the context, acceptance has a direct negative effect on variables of emotional and cognitive symptoms  but not on physical symptoms. This is possible since the concept of acceptance (derived from ACT) is aimed at improving emotional states . The preThe moderation analysis add that the variables of physical symptoms  were significantly and negatively associated with acceptance, only in patients from the rural area. That is, in rural patients, the greater the acceptance, the less pain, functional limitation, and physical fatigue. However, in urban patients there is no association between these variables. As mentioned above, the sociodemographic characteristics of patients from rural areas compared to those from urban areas differ significantly. The rural environment favors continuing a similar lifestyle despite the disease. By not feeling substantial changes in their daily lives, it is possible that patients perceive less severity in physical symptoms. The characteristics of the environment and the lifestyle of rural women favor acceptance of the disease and the impact of it does not significantly affect their daily lives . In thisTogether, the results presented suggest that the area of residence plays a role in the severity and management of symptoms in patients with FM. This has important practical implications to consider. The findings make it clear that the characteristics of FM patients in rural and urban settings differ so much that studies should not generalize the results in this population. It is considered necessary to develop specific treatment programs taking into account the characteristics of the patients depending on the demographic area. Specifically, it is recommended that interventions in patients in urban areas, due to the impact that the disease can have on their lifestyle, are focused on its acceptance. Instead, in rural areas, efforts should focus on increasing resources for specialized care for chronic pain.While acknowledging the relevant practical implications of the present research, this study certainly has some limitations. First, the associations must be interpreted according to the observational nature of the design, as this is not an experimental study. Furthermore, since the present study focuses exclusively on women with FM, the generalizability of the findings to other populations of musculoskeletal and non-musculoskeletal pain cannot be guaranteed. As the literature indicates, important differences have been revealed between this population and other populations with chronic pain . TherefoThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The study was approved by the Bioethics Committee of Rey Juan Carlos University . The patients/participants provided their written informed consent to participate in this study.PC and CP contributed equally to this article in terms of study conceptualization, design, and procurement of funding. SB and SP-C organized data collection. OL-R analyzed the data. DB contributed to the development of the assessment materials. All authors contributed to the writing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Pain was associated with distress, depression, anxiety, QoL, tumor stage (p < 0.001), and time since diagnosis (p = 0.012). Pain assessment and pain management should be a routine part of cancer treatment and cancer survivorship care plans.Pain is a common symptom in cancer patients, restricts daily life activities and reduces survival time. Identification of sociodemographic, medical and psychological correlates of pain among cancer patients in Germany could help identify subgroups most in need of pain management. In this multicenter, epidemiologic cross-sectional study, we assessed pain prevalence and severity, quality of life (QoL) and psychological distress in a sample of 3,745 cancer patients across all tumor entities. In total, 37.9% patients suffered from cancer-related pain and 56.1% suffered from non-specific pain. Younger, female, less educated and unemployed patients reported pain more frequently and more severe pain ( Pain is common among cancer patients and it is one of the most feared symptoms of cancer. Prevalence studies have demonstrated that pain still affects 37–64% of cancer patients , 2. PainPain prevalence and severity vary considerably, depending on socio-demographic and medical characteristics: Patients with head and neck, lung and breast cancer suffer more often from pain than patients with prostate cancer . A femalMultiple studies also showed that a cancer diagnosis results in increased levels of distress, depression and anxiety, especially in younger cancer patients and even years after diagnosis –19. ThisPain has been assessed in several studies in specific cancer populations, such as breast cancer and head and neck cancer patients , 25, 26 The purpose of this study was (1) to estimate the prevalence and severity of pain in a large representative sample of cancer patients in Germany, (2) to evaluate differences in demographic and medical characteristics between patients with and without pain, and (3) to investigate the associations between pain and distress, anxiety, depression and QoL in this population.In this multicenter, epidemiologic cross-sectional study, adult cancer patients were consecutively enrolled from acute care hospitals, outpatient cancer care facilities, and cancer rehabilitation clinics in Germany from 2007 to 2011. We used a proportional stratified random sample based on the nationwide incidence of all cancer diagnoses in Germany . In thisPatients with a confirmed diagnosis of a malignant tumor, aged 18–75 years and who were able to speak and read German, were eligible for this study. The exclusion of patients older than 75 years is due to the age limited validity of the Composite International Diagnostic Interview (CIDI) for the Assessment of Comorbid Mental Disorders in Oncology Patients (CIDI-O). Exclusion criteria were the presence of severe physical, cognitive, and/or verbal impairments that interfered with patients' ability to give informed consent.Sociodemographic information was collected through use of a standardized self-report questionnaire; medical information was gathered through medical records [see Mehnert et al.  for moreCRP was assessed with a modified version of the Brief Pain Inventory (BPI). Cleeland and Ryan  developeNSP was assessed with the pain scale from the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30). The EORTC QLQ-C30 is a well-validated instrument to measure cancer-related QoL . The queQoL was measured by the global health status/QoL scale from the EORTC QLQ – C30. It is comprised of two items and ranges from 0 to 100, where a higher score reflects a higher QoL.The German version of the General Anxiety Disorder-scale (GAD-7) was used to assess anxiety . The sevThe depression module of the German Patient Health Questionnaire (PHQ-9) consists of nine items assessing the frequency of depressive symptoms within the past 2 weeks . Items aThe German version of the NCCN Distress Thermometer is a valid and reliable measure for screening psychological distress in patients with cancer . The mean) and percentages (%) for categorical characteristics  and means (M) and standard deviations (SD) for continuous characteristics (pain severity). Chi-square tests were used to test associations of pain prevalence with sociodemographic and clinical characteristics. As a measure of effect size resulting from the Chi-square tests, we present Cramer's V. ANOVAs were used to test associations of pain severity with sociodemographic and clinical characteristics. We present Cohen's f as a measure of effect size resulting from the ANOVAs. Pearson's correlations were calculated to describe associations of pain severity with psychological characteristics. T-tests were conducted to test associations of pain prevalence with psychological characteristics. We present the Cohen's d as effect size. For all statistical tests, the result is considered as statistically significant with a 2-sided type-I-error-probability α <0.05. All analyses were performed with SPSS version 25.The dependent variables were pain prevalence and pain severity as measured with the BPI (CRP) and the pain scale from the EORTC QLQ-C30 (NSP). We report frequencies  reported CRP . PatientThe one-way ANOVA revealed that CRP severity varied significantly for sociodemographic and medical groups : YoungerWith regard to NSP, 847 (22.3%) patients reported mild pain, 839 (22.1%) reported moderate pain, and 442 (11.7%) reported severe pain. Associations of NSP with sociodemographic and medical variables were to a large part the same as the findings with regard to CRP, with a few exceptions: Unemployed patients and patients who were diagnosed with cancer more than 2 years ago reported higher NSP. The highest levels of NSP were found in patients with cancer of the female genital organs.Patients with CRP showed higher levels of depression and anxiety employment after cancer has been reported previously: Broemer et al.  found hiWith reference to tumor entities, we demonstrated lower pain prevalence rates and pain severity in prostate cancer (26%) compared to head and neck cancer (48.7%) and cancer of the female genital organs (46.0%). This is in line with van den Beuken-van Erverdingen et al.  who alsoPain prevalence and pain severity were associated with anxiety, depression, distress and QoL, whereby association with QoL was strongest. A study by Cox-Martin et al.  indicateOur study had some limitations. The comparability of our results with regard to CRP are limited since CRP assessment was two-staged in this study: only patients who answered the question on CRP in the affirmative answered the question on CRP severity. Equating CRP severity with zero in those participants who answered the question on CRP prevalence in the negative might underestimate CRP severity: Not everybody negating CRP would necessarily have checked zero on the questions regarding pain severity. It is a reasonable assumption that most of them would have done so, but this approach still leads to a reduced differentiation within the lower range of pain severity and potential underestimation of CRP. On the other hand, excluding 62.1% of the sample (those who answered the question on CRP in the negative) leads to a considerable overestimation of CRP severity and potentially biased result and is not advisable. Therefore, we conclude that including the whole sample by equating no CRP with a pain severity of zero is the more valid method of evaluating the BPI questionnaire. Another limitation of the present study is that CRP and NSP were assessed differently with regard to recall period and item number and range. The assessment of NSP prevalence was not dichotomous as was the assessment of CRP. This reduces the comparability of those two concepts. Additionally, the informative value of our results is restricted to patients younger than 76 years and to patients living in Germany between 2007 and 2011. Results with regard to cancer patients older than 75 years might differ substantially from our results, especially since age seems to impact pain experience.We assessed pain prevalence and severity in a heterogeneous group of cancer patients and provided insight into which cancer patients are particularly burdened with pain. Future studies need to carefully differentiate between CRP and NSP in cancer patients.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The Ethics Committees of all participating centers approved the study protocol: University Medical Centers of Freiburg, Heidelberg, Leipzig, and Würzburg. The patients/participants provided their written informed consent to participate in this study.LB, AH, and AM-T: conception and design. AM-T: administrative support. AM-T and UK: provision of study materials or patients and collection and assembly of data. LB and AH: statistical analysis. LB: manuscript writing. All authors: final approval of manuscript.This study was funded by a grant from the German Cancer Aid (Grant No: 107465) within the psychosocial oncology funding priority program.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cesarean section (CS) has been one of the most frequently performed major surgical interventions and causes severe postoperative pain. Spinal opioid and abdominal field block have been investigated as effective analgesia for postoperative pain and reduce the need for systemic medications and associated side effects. The aim of the current study is to compare spinal morphine (SM) and bilateral landmark oriented transversus abdominis plane (TAP) block for postoperative pain management.n = 56) or bilateral landmark-oriented TAP block with 20 ml of 0.25% of bupivacaine . A comparison of numerical variables between study groups was done using unpaired student t-test and Mann–Whitney test for symmetric and asymmetric data, respectively. Time to event variable was analyzed by using Kaplan–Meir's survival function. A p-value of < 0.05 was considered statistically significant.In this randomized controlled trial, 114 pregnant mothers scheduled for CS under spinal anesthesia were allocated randomly to receive either SM 0.1 mg . Median postoperative pain score during movement and rest shows statistically significant differences between groups (p < 0.001).A total of 114 patients were recruited and randomly assigned and received interventions. Among them, 108 patients completed this study. Time to first analgesic request was significantly shorter in the TAP block compared to SM. Twenty-four-hour median morphine consumption was reduced in the SM group compared to the TAP block (The addition of preservative-free 100 μg SM provides prolonged postoperative analgesia time, superior postoperative analgesia, and less postoperative opioid consumption compared to the TAP block. Cesarean section (CS) is a commonly performed major surgical procedure that results in substantial postoperative pain and patient dissatisfaction –3. The rManagement of postoperative pain is challenging, with 30–80% of women experiencing moderate-to-severe pain . ApproxiAlthough different options for pain management exist, the ideal form of postoperative analgesia is still unknown. The clinical efficacy of transverse abdominis plane (TAP) block and SM has been demonstrated in different clinical trials of patients undergoing abdominal surgery including CS showed different effects regarding postoperative analgesic consumption and pain score , 14. In via Pfannenstiel incision under spinal anesthesia were included. Patients who refused to participate, ASA 3 and 4 patients, failure to administer spinal anesthesia, patients with a history of chronic pain disorder, patients who were allergic to local anesthetics and morphine, patients with cognitive impairment, and patients with preeclampsia were excluded from this trial.A prospective, parallel-randomized, controlled, investigator-blinded, single-center trial was conducted from January 2020 to July 2020. Study participants were included using a systematic random sampling method from consecutive patients. All parturients (aged between 18 and 45 years) who underwent elective cesarean delivery via double dilution procedures. It was started by drawing 1 ml of 10 mg/ml morphine in a 10-ml syringe, and this was diluted with 9 ml of 0.9% normal saline. After mixing, again 1 ml was drawn from a syringe and diluted with 9 ml of 0.9% normal saline. Finally, after mixing, 1 ml (100 mcg) of the mixture was aspirated and added with bupivacaine.Preanesthetic evaluation was done in the morning on the day of surgery, and eligibility criteria were checked before recruiting the study participants. Informed consent was obtained from each participant. Vital signs, organ function tests, history, and physical examinations were reviewed. On arrival to the operating room, parturients were premedicated with IV cimetidine (200 mg), metoclopramide (10 mg), dexamethasone (4 mg), and ondansetron 0.1 mg/kg 30 min before the induction of anesthesia for prevention of aspiration, nausea, vomiting, and pruritus according to the institutional protocol. Non-participating researchers prepare morphine 2), heart rate, heart rhythm, end-tidal carbon dioxide, and temperatures were monitored every 5 min and recorded every 10 min. Spinal anesthesia was then administered between L3 and L4 with 12.5 mg of 0.5% heavy bupivacaine with 100 μg preservative-free morphine by using a 24-gauge spinal needle for spinal morphine (SM) group and spinal anesthesia with 12.5 mg of 0.5% heavy bupivacaine and bilateral landmark-oriented TAP block with 20 ml, 0.25% bupivacaine at each side for the TAP group at the end of the operation. The blocks were performed by an anesthetist with >2 years of experience in the performance of TAP block.Standard monitoring non-invasive blood pressure (NIBP), oxygen saturation  and managed according to the protocol. After the parturient was discharged from operation theater, pain severity was assessed by NRS at 2nd, 6th, 12th, and 24th h at rest and movement. Those patients with NRS score beyond 3 points were managed with tramadol 1 mg/kg IV, diclofenac 1 mg/kg IV, and paracetamol 20 mg/kg PO. Patients with NRS scores beyond 7 points were managed with diclofenac 1 mg/kg IV, paracetamol 20 mg/kg PO, and morphine 0.1 mg/kg IV as per the protocol. Tramadol that was used during the postoperative period was converted to morphine equivalent dose using a 0.1 conversion ratio . FollowiPatients were allocated using computer-generated randomization. During allocation, the researcher did not participate in either SM or TAP block. To achieve blinding to the intervention, a drape was used to prevent women from visualizing the performance of the TAP block. Various data collectors were employed during the intraoperative and postoperative periods. The intraoperative caregiver was not blinded to the intervention group.The primary outcome was the time to first analgesic request. Time to first analgesic request was recorded upon patient request. Secondary outcomes were postoperative pain intensity, analgesic consumption, the proportion of patients who achieved adequate analgesia, adverse effects , and maternal satisfaction with the quality of analgesia. Postoperative pain intensity was measured by a standardized NRS at 2, 6, 12, and 24 h postoperatively.To show a clinically significant 50% difference in time to first analgesic request between SM and TAP block groups, with 80% statistical power and a two-tailed significance level of 5%, each group required 57 subjects and 114 subjects in total.t-test, and Mann–Whitney test was used for pain intensity and morphine equivalent analgesic consumption. Frequency and percentages were used to describe categorical variables. Statistical difference between groups was tested by Chi-square and Fisher exact test according to the nature of data. Time to event variable was analyzed using Kaplan–Meir's survival function. Generalized Estimation Equation (GEE) were used to model the repeatedly assessed NRS pain scores longitudinally to investigate the interactive effects of the intervention group and repeated time. Autoregressive Order 1 (AR1) structure of working correlation matrix was assumed and SEs were used. The independent variables were the follow-up time and intervention group. The effects and interactions between follow-up time to the intervention were assessed. A p-value of < 0.05 was considered statistically significant.Data were checked, coded, entered, and analyzed by the IBM SPSS version 25 software package . The data were tested for normality by using the Shapiro–Wilk test and homogeneity of variance by Levene's test for continuous data. Numerical data were described in terms of mean ± SD for symmetric and median  for asymmetric data. A comparison of sociodemographic variables, hemodynamic data, intraoperative tramadol consumption, duration of surgery, and Apgar score between study groups was performed by using unpaired Student's The study received approval from the Dilla University Institutional Review Board . In addition, this study has been prospectively registered in December 2019 at Pan African Clinical Trial Registry with the identification number PACTR202002616299138. The purpose, importance, and risk of the study were explained to each participant prior to obtaining written informed consent. Participants were informed that they could withdraw from the study without any restrictions at any time.Out of 114 patients who were screened for this prospective, randomized, controlled study, 108 patients were finally recruited and randomly assigned to the groups . Among ap-value of > 0.05   . The cump < 0.001). Similarly, in the 6, 12, and 24 h postoperatively, median (IQR) NRS score was 1 (0–1) vs. 3 (2–4) (p < 0.001), 2 (1–3) vs. 4 (3–4) (p < 0.001), and 3 (3–3) vs. 4 (3–4) (p < 0.001) in the SM and TAP groups, respectively. Median postoperative pain scores during movement at 2nd, 6th, 12th, and 24th h were 0.5 (0–1) vs. 2 (1–3) (p < 0.001), 1 (0–1) vs. 3 (2–4) (p < 0.001), 2 (2–3) vs. 4 (3–5) (p < 0.001), and 3 (3–4) vs. 4 (3–5) (p < 0.001) in the SM and TAP groups, respectively  in the SM group and 2 (1–2) in the TAP group . Generalized Estimation Equation (GEE) indicated that there was a statistically significant interaction between the intervention group and repeated measure at 6th and 12th h .After adjustment of pain score at rest for repeated measurements, generalized estimating equation model showed that NRS score was 0.9 units lower in the SM group than in the TAP group during the first 24-h postoperative period in NRS pain scores at rest  in the GEE model.There were statistically significant effects of repeated measurement in pain score at rest 2nd h   .2 = 14.06, p < 0.001), 6th h , and 12th h .The GEE model showed that there was a statistically significant interaction between the intervention group and repeated measurement during movement pain score at 2nd h  and 6th h postoperatively .There were statistically significant effects of repeated measurement on pain intensity score (NRS) during movement at 2nd h  mg compared to the TAP block group 10 (10–15) mg (p < 0.001) (In the immediate postoperative period (2 h), median tramadol consumption was 0 ± (0) mg in the SM group and 12.5 ± (21.8) mg in the TAP group (< 0.001) .p < 0.001).At rest, 62.6% of patients in the SM group reported pain scores ≤3 compared with 37.4% in the TAP group. The SM group was significantly associated with adequate analgesia at rest (pain scores ≤3) compared to the TAP group . On movement, 65.8% of patients in the SM group had pain scores ≤3 as opposed to 34.2% in the TAP group. The SM group was significantly associated with adequate analgesia during movement (pain scores ≤ 3) compared to the TAP group , as a result of effective analgesia in the postoperative period. Similar to our findings, an earlier study found that the TAP block was associated with greater supplemental morphine equivalent requirements of 7.5 mg (95% CI 4.8–10.2) than the SM 2.7 mg (95% CI 1.0–4.3) .Regarding postoperative complications , results between the two groups did not show any clinically significant difference . This caIn our study, all patients received 4 mg of ondansetron before the procedure for prophylaxis of vomiting and pruritus. Postoperative maternal satisfaction with the quality of pain relief was significantly different between the two intervention groups. Most of the patients in the SM group were highly satisfied with the quality of pain control compared to that of the TAP group. In contrary to our study, previous studies have shown maternal satisfaction was similar for both SM and TAP groups –20. The a priori expected to be more favorable for the SM group. Therefore, we recommend future researches to assess PDPH and explore other comparisons like SM with the TAP block of other dosages.This is a single-center study. Although the study population is inclusive, the external generalizability of these results has taken into account the size of the study population. However, the results of the study are presented consistently. In this study, ultrasound was not used for the TAP block because of the lack of ultrasound for nerve block in the study area. Organ penetration and other rare complications associated with the TAP block were not examined. We did not assess the incidence of postdural puncture headache (PDPH); however, we used the same gauge needles for both groups to ensure that they were equally affected. Another limitation of our study was that we did not assess the success rate or sensory spread of the resulting block, because a residual sensory block from spinal anesthetic might last for hours after surgery. Additionally, there were difficulties in adequately blinding intraoperative caregivers and data collectors. However, neither the patients nor postoperative data collectors were aware of group allocations. Another limitation of this study was we did not assess the comparison of SM , with a blind TAP block (a technique known to be more reliable with the guidance of ultrasound and that only might control the somatic pain) is We conclude that the addition of preservative-free 100 μg SM for cesarean delivery under spinal anesthesia provides superior analgesia, prolonged time to first analgesic request, and less postoperative opioid consumption compared to that of the landmark TAP block. No significant differences in postoperative complications like nausea, vomiting, and pruritus between groups were found. Thus, we recommend the use of preservative-free 100 μg SM for parturients who undergo CS under spinal anesthesia to achieve prolonged time to first analgesic request, for better postoperative analgesia, and to reduce the side effects of analgesic consumption.https://apps.who.int/trialsearch/Trial2.aspx?TrialID$=$PACTR202002616299138).This study is registered with the Pan African Clinical Trial Registry on 24 December 2019 and the registration number was PACTR202002616299138 (The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Dilla University Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.BJ and FM have made substantial contributions in conception, design, analysis, interpretation of data, critical review, and editing of the manuscript drafts for scientific merit and depth. SA, AM, TR, HT, and MO have made substantial intellectual contributions to the acquisition of data, interpretation of data, and preparing the manuscript for this study. All authors have read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Painful post-traumatic trigeminal neuropathy (PTTN) is a known complication of dental implant therapy. Besides cases resulting of nerve damage during surgery or implant placement, some patients report delayed neuropathic-like symptoms only after implant loading i.e. crown placement. The present retrospective study aimed at describing the clinical features of pain experienced by these patients. The cohort of patients consulting for chronic orofacial pain at the Groupe Hospitalier Pitié-Salpêtrière  between 2015 and 2020 , was screened for patients with history of dental implant placement and persistent pain. Patients with no pain after surgery for 6 months and pain resulting from the loading of the implant, were included. Among 675 files of patients screened, 5 fulfilled inclusion criteria. All patients were women, mean age 62.4 ± 9.8 y.o, and reported trigeminal neuropathic-like persistent pain. Intensity of pain was described as moderate to severe, with pin and needles, burning and tingling, and electric shocks as main symptoms.These results suggest that implant loading can trigger trigeminal neuropathy, in a previously sensitized nerve. Putative neurophysiological basis of the phenomenon is discussed. Key words:Neuropathic pain, trigeminal nerve, lesion, dental implant, implant loading, allodynia. Dental Implant therapy (DIT) has become over the years a well-defined and accepted therapy with increasing indications. The success rate of DIT is overall high and the failures are mainly due to periimplantitis and treatment planning errors ,2. Post-Painful Post Traumatic Trigeminal Neuropathy (PTTN) has been defined in the ICHD3, as persistent pain occurring in a delay of 3-6 months in the area of a documented trigeminal nerve lesion ,12. ThisPTTN after DIT is usually caused by trigeminal nerve damage during implant surgery either by direct nerve lesion caused by the drill or the implant or by indirect damage. The latter may have different origins for example compression of the nerve by bone debris or edema , thermal injury caused by local heat during implant drilling ,15,16, lBesides these cases in which persistent pain can be attributed to the nerve damage caused by implant surgery, we noticed in our secondary orofacial pain consultation that several patients reported onset of trigeminal neuropathic-like pain only after implant loading, i.e. after the placement of the crown or bridge; the pain thus could not be attributable to nerve damage. This intriguing observations prompted us to document the phenomenon. A retrospective cohort study was therefore undertaken in order to provide a clinical description of these patients.This cross sectional observational retrospective cohort study was approved by an IRB , registered in the national data protection agency (CNIL), and followed the STROBE recommendations for observational studies. It complied with the ethical principles of the Helsinki declaration and Good Clinical Practice. Anonymity of participants was respected throughout the course of the study.-Patient selection The COFP consultation of the dental service of the Pitié-Salpêtrière Hospital (GHPS) is a clinical setting for either inpatients or outpatients, mainly referred by dentists, physicians  for complex pain. Clinical records from 2015 to 2020 were screened between September 2019 and June 2020 according to the following inclusion and exclusion criteria.Inclusion criteria.• history of dental implant placement • absence of pain before implant placement • pain in the area of implants • absence of persistent pain in a 6-month period after implant placement, except in the 3 weeks following surgeryExclusion criteria.• Patients under 18 y.o.• Patients with impaired communication • Pain with pain before implantation and/or loading• Pain occurring within 4 weeks after dental implant loading• Patients suffering from other chronic painful oral disease, unless well identified such as DTM • Pain arising from another region than the trigeminal nerve.• Pain arising from a different branch of the trigeminal nerve than concerned by the implant • Periimplantitis, assesssed clinically and radiographically • Interference of the implant with the nerve trajectory suggestive of a nerve lesion -Data extraction The data collection included demographic data ; medical status, dental and loco-regional history; medications; clinical features of pain including intensity assessed on a 0-10 numerical scale (NS), quality, temporal pattern, location, delay of apparition and time course; associated autonomic signs; aggravating and relieving factors; DN4 questionnaire as used in a previous study for chronic orofacial pain .-Sample Among the 675 patients attending the consultation during the period of the study, 5 fulfilled inclusion criteria and constituted the final sample. They were all women, aging from 53 to 74 years with medical characteristics and pain phenotypes reported in -Onset of the painno patient reported a painful surgery and a six-month period minimum was respected between the implant loading, with no pain during this period (inclusion criteria). All patients experienced oral discomfort a few days after implant loading, and complained to their practitioner. Prosthetic elements were removed in all cases without long term improvement. Implants were removed in 4 cases resulting in a reduction in painful sensations for 2 patients. In order to relieve pain, the patients consulted several specialists such as GP, stomatologists, healers, osteopath, acupuncturist, changed dentist, were referred to a pain center were specific prescriptions were given.-Pain phenotype All patients reported continuous pain, either stable (1 patient) increasing during the day (1 patient) or with fluctuations with no specific temporal pattern (3 patients). Intensity ranged from 2 to 9 on the 0-1 NS, oral function (speech and mastication) exacerbated the pain in 2 patients when food intake  relieved the pain in two patients. One had no aggravating/exacerbating factors). The most described sensations were pin and needles (4/5) > burning pain and tingling (3/5) > electric shocks (2/5)>cold pain and mechanical sensation not captured by DN4 described as incomfort, heaviness, tightness, pulling-LocalizationAll patients reported pain in the area of the implantation site, at the maxilla or mandible. In two patients the pain area was circumscribed to this site when it radiated in the ipsilateral trigeminal branch in three patients and also in the opposite arch in one patient.-Treatments.Classical treatments for NP were attempted  but none were satisfactorily although the pain was attenuated in 2 patients.In this retrospective study, we identified a subgroup of patients with persistent orofacial pain after dental implant therapy evoking PTTN although not attributed to the surgical procedure per se, but by implant loading, i.e. after the fitting of the implant-supported prosthetic crown. A similar case has previously been mentioned in the literature .-Clinical considerationsAccording to the symptoms and clinical behavior, the patients were diagnosed as NP in line with IASP recommendations . Althoug-Pathophysiological hypothesesA simple explanation is difficult to find, first because there was no identical semiology, either for intensity, pattern or quality; second, because further interventions were sometimes performed in order to relieve the pain (example JD extraction 38). It is therefore possible that these interventions worsened the initial symptomatology. It is also known that neuropathic changes elicit a diversity of sensations reflecting the diversity of mechanisms and types of nerve fibers involved . KeepingThe pathophysiology of PTTN triggered by nerve lesions is complex and involves peripheral and central mechanisms . Among tet al. (An interesting observation is provided by Tashima et al.  who showet al. , have seet al. ,29. Chanet al. -35, haveet al. .If neuropathic changes in primary afferents and spinal/trigeminal are well documented, other mechanisms involving suprasegmental neuronal networks might also occur. It is for example known that tooth removal and its replacement by implant both lead to peripheral nerve degenerative/regenerative pathways as well as somato-sensory cortex reorganization . Alterat-Priming Since the symptoms did not appear immediately, the concept of priming can be evoked. As previously proposed in other conditions, the inflammatory sensitization of primary afferents might favor the occurrence of NP in case of a later traumatic event . In the -Limitations.The retrospective study design limits the collection of clinical information. Main data are declarative patient-based data.This study supports the hypothesis that implant loading may be responsible for the development of neuropathic pain. A two-step mechanism can be evoked with a sensitization of primary sensory afferents by neuro-inflammatory mechanisms, secondary activated by mechanical afferents after implant loading.


For most patients, tennis elbow (TE) resolves within 6 months of onset. For those with persistent and painful TE, nonsurgical treatment options are limited. Thousands of studies have tried to find effective treatments for TE but have usually failed. In this study, we tested the hypothesis that injections with hyaluronic acid (HA) would be effective at reducing pain from chronic TE.Patients with a minimum of six months of pain from TE and with a pain level of 50 or greater (out of 100) were included in the study. They were randomized equally into one of two treatment groups: injection with HA or injection with saline control. Follow-up was conducted at 3, 6 and 12 months from the initial injection. Both the patient and the examiner at the follow-up visits were blinded to the treatment arm. The primary outcome measure was the visual analog scale (VAS pain) score at one year. Additional outcome measures included the shortened Disabilities of the Arm, Shoulder and Hand questionnaire (QuickDASH) and Patient Rated Tennis Elbow Evaluation (PRTEE) scores.Eighteen patients were randomized into the HA injection treatment arm, and 17 (94%) completed the study. The average age was 51.9 years, and 10 of the subjects were male. Patients had an average of 28.1 months of pain before entering the study. The VAS score in the HA group decreased from a baseline of 76.4–14.3 at 12 months. All 17 patients in the HA group showed VAS score reductions above the minimal clinically important difference (MCID) of at least 18. The PRTEE score improved from 67 to 28.1. The QuickDASH score improved from 53.7 to 22.5. Follow-up in the saline group was less than 50% and was therefore not used as a comparator.HA injections yielded significant success in pain relief by three months. Patients continued to improve for the 12-month duration of the study. This study indicates that patients with chronic lateral epicondylitis may benefit from receiving injections of hyaluronic acid rather than having to undergo surgery. Tennis elbow (TE) is a widespread and painful condition. Although usually a self-limited condition, in approximately 20% of cases, the pain remains chronic (ref). Nirschl , in his Tennis elbow is considered to be self-limiting; in 80% of patients, the symptoms resolve within six to twelve months . HoweverThis study was designed according to the Consolidated Standards of Reporting Trials (CONSORT) guidelines . This clThe criteria for diagnosis included pain and tenderness at the lateral epicondyle that worsened with resisted wrist or finger extension (with the elbow in the extended position). The inclusion criteria were age over 18 years, chronic pain defined as six months or longer, and pain (average pain over the past week when using the hand) measured on the visual analog scale (VAS) at 50 mm or greater (out of 100 mm).Exclusion criteria included elbow steroid injection less than three months prior to starting the study, prior elbow surgery, inflammatory conditions such as rheumatoid arthritis or lupus, and allergies to birds, feathers or egg products. If the patient had complaints of pain and significant tenderness on exam in the area of the radial neck, then a component of radial tunnel syndrome was assumed, and those patients were excluded from the study. Patients with pain from other areas, such as the radiocapitellar joint or medial epicondyle, were also excluded.All injections were performed using syringes that were masked and numbered. The patients were blinded to the treatment arm. The return evaluations at 3, 6 and 12 months were performed by an experienced hand specialist who was also blinded to the treatment arm.This study used Intragel . The formulation has a molecular weight averaging 800–1200 kDaltons and a concentration of 16 mg per 2 cc. The author (GZ) performed all injections. The injections were performed in a similar fashion for both the HA and saline groups. First, the point of maximum tenderness at the lateral epicondyle was identified and marked. After local preparation with alcohol, 1 cc of lidocaine 1% was placed both superficially and deep into the tendon substance. Using a separate and preloaded syringe, 2 cc of either HA or saline was injected using a fanning technique of 3 perforations into the area of maximal tenderness approximately 1 cm distal to the lateral epicondyle. Each participant was injected three times, two weeks apart. When planning the study, we reviewed all the clinical studies to date, and the number of injections performed was between one and six per patient.Patients were not referred for any additional treatment during the study period. Most had tried therapy and steroid injections prior to enrollment.General demographic data included age, sex, handedness, type of work, symptomatic side, and participation in racquet sports Table .Table 1CThe primary outcome measure was the VAS score for pain when the subject was asked, “What is the average pain you experienced the past week while gripping or actively using your hand?” Secondary outcome measures included the brief form of the Disabilities of the Arm, Shoulder, and Hand questionnaire (QuickDASH)  and the The QuickDASH is an 11-question short version of the longer 30-question DASH. The score ranges from 0 (no disability) to 100 (most severe disability). The PRTEE is a 15-question survey that evaluates pain and function on a 10-point VAS. The score ranges from 0 (no pain and maximum function) to 100 (maximum pain and minimum function).The primary endpoint was a reduction in VAS pain three months after the initial injection.Secondary outcomes included differences in HA treatment outcomes in terms of VAS pain at six and 12 months and for PRTEE and QuickDASH at 3, 6 and 12 months post-injection. We also calculated a 25% reduction in VAS pain from baseline for HA versus saline to allow comparison to the Peerbooms et al. 2010  results . They evaluated the treatment of chronic TE in racquet sport athletes using a total of two HA injections one week apart. They used pain VAS scores as their primary endpoint. Using standard deviation data from their study, we calculated the sample size needed to power this study. With the null hypothesis that the HA group would improve relative to the control group (by VAS 18 or greater) at 3 months post-injection, the significance level, One of the few prospective studies on HA performed to date was conducted by Petrella et al. . They evDifferences in baseline characteristics were assessed with Fisher’s test for categorical variables and the T test or Wilcoxon test for continuous variables, depending on the distribution of the data. The T test was used to evaluate differences in outcome measures.The enrollment period was from January 18, 2017, to December 3, 2018, and the study period continued for one year from the final injection until December 2019. In the saline group, 17 patients were initially enrolled. There was increasing drop-out at each follow-up visit so that by the 12-month visit, only eight of the 17 patients (47%) returned for follow-up  to 42.6 (SD 25.5) at three months (p = 0.001).The average pain score in the HA group continued to improve over time Fig. . The aveMCID : All 17 patients in the HA group showed VAS score improvement above an MCID of at least 18 [.least 18 ..Twenty-five percent reduction: Using Peerbooms et al. 2010 [al. 2010  criteriaQuickDASH: The QuickDASH score improved over time (Fig. ime Fig. , in the PRTEE: The PRTEE score improved over time (Fig. ime Fig. . The HA Both the QuickDASH and the PRTEE measure pain and function. The PRTEE is considered a more specific measure for tennis elbow and theoretically would be more sensitive to changes when evaluating patients limited by TE. In this case, both measures improved since patients improved in both groups with less pain and more function.The results of this prospective study show that HA injections were effective at relieving pain and improving function in patients with chronic TE. Despite an average of more than two years of pain, the VAS score improved from 76.4 to 14.3.A patient with chronic tennis elbow has few proven options other than surgery. Coombes et al.  performeSteroid injections continue to be the most common treatment, and PRP has become popular despite insufficient scientific support. In a prospective, double blind randomized clinical trial of 64 patients with less than six months of pain, Lindenhovius et al. , 26, 27.In a review of the English-language literature, we found eleven relevant studies that evaluated HA for tendinopathies. Three used HA for lateral epicondylitis , 16, 28;Petrella et al.  performeThe saline group was not compared to the HA group since it was considered an unreliable comparator. We tried to contact the lost patients and offer them treatment with HA or at least determine why they did not return, but they would not respond to either phone or email contact, which we purposely limited to two efforts each. We can only speculate as to the reasons for the high saline drop-out compared to the low-drop out for the successfully treated HA group.There is some evidence that saline for TE may not be a true placebo but might also have therapeutic benefits. It therefore might not be the ideal comparator. Gao et al.  and AcosAlthough the focus here is to compare HA injection to other nonsurgical treatments, it is worth comparing the results here to surgical treatment. Ruch et al.  comparedThere are no studies to date that report the results of a prospective study of HA treatment for LE in non-racquet sport athletes with a follow-up of one year. The only other prospective study on HA treatment was performed by Patrella on racquet sport athletes . This stThe many patients lost to follow-up in the saline group limited this study to having a placebo group for comparison. However, as noted, saline may have some therapeutic benefits of uncertain duration and may not be the ideal placebo control. In addition, given our strict inclusion and exclusion criteria, there was lower than targeted patient recruitment. However, the HA group showed significant improvement using all measures.We conclude that, based on this prospective study with one year of follow-up, HA proved effective at treating chronic TE. Other than the pain of injection, no negative side effects of HA injection were observed over the course of the study. We feel that despite the limitations of this study, there is a large benefit and minimal risk that favors injecting HA for chronic tennis elbow. However, we recommend that a larger study with appropriate placebo control be performed. Tennis elbow and other enthesopathies remain difficult to treat. We hope this study stimulates further research in this important area to investigate the use of HA injections to treat this painful condition.