Local anesthetic wound infusion has become an invaluable technique in multimodal analgesia. The effectiveness of wound infusion of 0.2% ropivacaine delivered by patient controlled analgesia (PCA) pump has not been evaluated in minimally invasive cardiac surgery. We tested the hypothesis that 0.2% ropivacaine wound infusion by PCA pump reduces the cumulative dose of opioid needed in the first 48 h after minithoracothomy aortic valve replacement (AVR).− 1 continuously and 5 ml of bolus with 60 min lockout. Pain levels were assessed and recorded hourly by Numeric Rating Scale (NRS). If NRS score was higher than three the patient was administered 3 mg of opioid piritramide repeated and titrated as needed until pain relief was achieved. The primary outcome was the cumulative dose of the opioid piritramide in the first 48 h after surgery. Secondary outcomes were frequency of NRS scores higher than three, patient’s satisfaction with pain relief, hospital length of stay, side effects related to the local anesthetic and complications related to the wound catheter.In this prospective, randomized, double-blind, placebo-controlled study, 70 adult patients  were analyzed. Patients were randomized to receive 0.2% ropivacaine or 0.9% saline wound infusion by PCA pump for 48 h postoperatively. PCA pump was programmed at 5 ml hp < 0.001) in the ropivacaine (R) group median 3 mg (IQR 6 mg) vs. 9 mg (IQR 9 mg). The number of episodes of pain where NRS score was greater than three median 2 (IQR 2), vs 3 (IQR 3), (p = 0.002) in the first 48 h after surgery were significantly lower in the ropivacaine group, compared to control. Patient satisfaction with pain relief in our study was high. There were no wound infections and no side-effects from the local anesthetic.The cumulative dose of the opioid piritramide in the first 48 h after minithoracotomy AVR was significantly lower (Wound infusion of local anesthetic by PCA pump significantly reduced opioid dose needed and improves pain control postoperatively. We have also shown that it is a feasible method of analgesia and it should be considered in the multimodal pain control strategy following minimally invasive cardiac surgery.ClinicalTrials.gov NCT03079830, date of registration: March 15, 2017. Retrospecitvely registered. Multimodality in pain management, during and after surgery, has long been established and well accepted . Since, Delivering local anesthetic through a wound catheter was proven to be a successful way of postoperative pain relief throughout most surgical fields –17. In cWe designed a prospective, randomized, double-blind, placebo-controlled trial, to analyze the effectiveness of wound infusion of 0.2% ropivacaine delivered by patient control analgesia (PCA) pump for pain relief after minimally invasive right anterior minithoracotomy aortic valve replacement (AVR).ClinicalTrials.gov (NCT03079830). The study was conducted in a tertiary level university hospital from March 2017 to January 2018. With this prospective, randomized, double-blind, placebo-controlled study we analyzed the effectiveness of wound infusion of local anesthtetic 0,2% ropivacaine after minimally invasive - right anterior minithoracotomy AVR. The study adheres to the CONSORT guidelines for reporting research.This study was approved by the National Medical Ethics Committee of Republic of Slovenia  and registered at All patients were preoperatively given a detailed description of the study by an anesthetist. After obtaining written consent, the patients were familiarized with the numeric rating scale (NRS) for pain evaluation where “0” represents no pain and “10” represents worst possible pain.The protocol we describe was a result of a small pilot study we carried out before the main study. Inclusion criteria were all adult patients scheduled to have an elective right anterior minithoracotomy AVR who consented to be included in the study. Preoperative exclusion criteria were patients not consenting to the study, emergency surgery, patients allergic to local anesthetic and patients with chronic pain syndromes. Postoperative exclusion criteria were reoperation in the first 48 h after surgery and prolonged need for intubation postoperatively. In total 76 adult patients scheduled to have an elective right anterior minithoracotomy AVR were randomly allocated into two groups. All patients were operated by the same surgical team and all patients received the same sutureless aortic valve .− 1, ethomidate 0.2 mg kg− 1 were used as induction agents and rocuronium 0.6 mg kg− 1 was used as neuromuscular blocking drug. Intubation was performed with a single lumen tube. Total intravenous anesthesia was maintained with 0.3 μg kg− 1 min− 1 remifentanyl and 5 mg kg− 1 h− 1 propofol. Standard haemodynamic monitoring for cardiac surgery was used during the procedure. Our standard monitoring includes direct arterial blood pressure, central venous pressure, transoesophageal echocardiography, body temperature, urinary catheter and cerebral oximeter.All patients were premedicated one hour before the surgery with 5 mg diazepam orally. Fentanyl 5–10 μg kg− 1. Before stopping the remifentanil infusion at the end of the operation all patients were administered 2.5 g i.v. metamizole, a non-opioid analgesic. After the operation patients were admitted to the ICU. Once patients met the standard extubation protocol requirements they were extubated  by using an introducer needle. The catheter was placed above the ribs in the deep subcutaneous tissue followed by a bolus of 10 ml of 0.75% ropivacaine through the catheter  - 38 patients and Control group - C  - 38 patients. A dedicated nurse that was not part of the performing anesthetic team was in charge of the randomization process. Randomization was done by covariate adaptive randomization using an on-line program for randomization at − 1 and a bolus of 5 ml if needed with a lock out time of 60 min.The anesthetist in the operating theatre, the intensivists and the nurses in the ICU and HDU were all blinded to which group a patient was randomized to. The PCA pump was programmed the same way for both groups, to continuously administer the mixture at 5 ml h− 1 of 0.2% ropivacaine continuously per PCA pump through the wound catheter and a single 5 ml bolus if needed with 60 min of lock-out time.1. Patients in the ropivacaine group were administered 5 ml h− 1 of 0.9% saline continuously per PCA pump through the wound catheter and a single 5 ml bolus if needed with 60 min of lock-out time.2. Patients in the 0,9% saline group were administered 5 ml hPostoperatively in the ICU, patients in both groups regularly received metamizole 2,5 g/12 h i.v. Once the patient was awake, extubated and able to communicate, the ICU nurse hourly assessed and recorded the pain level by NRS score, except when patients were asleep. If the pain level was higher than three, the patient at first administered a bolus of 5 ml of the mixture delivered by the PCA pump through the wound catheter. If the NRS pain score remained higher than three, 15 min after the PCA bolus, the patient was administered i.v. bolus of 3 mg piritramide - an opioid 0.75 times as potent as morphine , by a nu° and analyzed after all the samples from all 20 patients were taken.The dedicated nurse using Stratified Randomization randomly selected 20 patients to have total plasma ropivacaine concentration measured (ten from each group). Also 20 patients (ten from each group) were randomly selected, using the same method, to have the tips of wound catheters’ sent for microbiology analysis after removal. Venous blood samples for total plasma ropivacaine concentration were taken at 1 h, 24 h and 48 h after surgery. The blood samples were centrifuged immediately at 3000 rpm for 5 min and plasma was aspirated and pipetted into a separate tube. The tubes with the plasma samples were then frozen at − 60The primary outcome of our study was the cumulative dose of the opioid piritramide required in the 48 h after surgery, compared between the two groups. Our secondary outcomes were the frequency of NRS scores higher than three, patients’ satisfaction with the pain relief, the time to recovery and discharge from hospital, side effects related to local anesthetic and complications related to the wound catheter. Patients’ satisfaction with the pain relief was assessed on the third postoperative day by anesthetist trainees, that were blinded of the treatment allocation, on a patient satisfaction scale with the possible answers ranging from 1.completely satisfied, 2.satisfied, 3.neither satisfied nor dissatisfied, 4.dissatisfied, to 5.completely dissatisfied.Before carrying out the main study, we performed a small pilot study with 20 patients, to assess the feasibility of the method and for sample size calculations. Results are based on the primary outcome, piritramide consumption in the first 48 h after surgery. To achieve 85% of statistical power at least 35 patients per group had to be included into the study. Effect size for our calculaction was 1.09. Groups of patients were compared by Mann-Whitney U test or χ2 test where appropriate. P -value below 0.05 was used for statistical significance. Statistical analysis was performed using the R project, a language and environment for statistical computing - R Foundation for Statistical Computing, Vienna, Austria.Overall, 76 eligible patients consented to participate in the study. Postoperatively 3 patients from the ropivacaine group and 2 patients from the 0.9% saline group were excluded due to occlusion of the wound catheter. Also, one patient from the 0.9% saline group was excluded due to prolonged need for intubation postoperatively, not related to the wound catheter. Thirty-five patients in each group completed the study and their results were analyzed  in the ropivacaine group. The median cumulative dose of piritramide in 48 h in the ropivacaine group was 3 mg (IQR 6 mg). The median dose of piritramide in the 0.9% saline group was 9 mg (IQR 9 mg). We found that the difference between the two groups was statistically significant (p < 0.001), . The median number of episodes of pain where NRS score was greater than three in the ropivacaine group was 2 (IQR2). The median in the 0.9% saline group was 3 (IQR 3) . The median patient satisfaction with the pain relief in the 0.9% saline group was 2 (IQR 1). There was no significant difference between the two groups regarding pain relief satisfaction, Mann-Whitney U test, p = 0.652 . The median length of hospital stay in the 0.9% saline group was 8 days (IQR 2 days). There was no significant difference between the two groups in length of hospital stay, Mann-Whitney U test, g l− 1 as suggested by an earlier study on volunteers [There were no clinical signs of local anesthetic neurotoxicity nor cardiotoxicity in any one of the patients studied. No sample reached the maximum tolerated total plasma level of ropivacaine of 2.2 mlunteers . There wThe results of our study have shown that by administering a local anesthetic using a PCA pump there was a significant reduction of the opioid dose needed postoperatively. We also found significantly lower frequency of NRS scores higher than three in the ropivacaine group.In recent decade, minimally invasive cardiac surgery has gained momentum in everday clincal practice mainly due to continuously growing medical technological innovations, progress in surgical techniques and advancement in anesthesiological experitse, involving modified patient monitoring, innovations in anesthesia drug delivery pathways, and utilization of short-acting anesthetics and multimodality in pain management.Effective postoperative pain relief through multimodal approach is the goal every perioperative team aims to achieve. Improving postoperative analgesia leads to faster mobilizing, higher patient satisfaction and better surgical results , 25. EveWe did not observe any wound infections or impaired wound healing in this study. There were no signs of local anesthetic toxicity, based on continuous clinical assessment and monitoring. The patient satisfaction was similar in both groups, which proves that multimodal approach based on a local anesthetic wound infusion is not inferior to the more traditional i.v. opioid centered analgesia. However, our study did not show a shortened length of hospital stay for the local anesthetic group compared to the control group. This can be attributed to the fact that even the patients in the control group did not receive a large cumulative dose of opioid. We acknowledge that there was also the effect of the bolus of 0.75% ropivacaine that we administered to both groups at the end of the operation. It was done for ethical reasons as we were using an ultra short-acting opioid during the surgery. It is also important for the whole postoperative team  to follow the advances in surgical minimally invasive techniques as certain rehabilitation procedures can be carried out earlier than after full sternotomy procedures. We argue that the minimally invasive cardiac surgery needs a separate recovery pathway from the classic cardiac surgery approach with full sternotomy. Other medical centers have already reported shorter length of hospital stay than in our study after minithoracotomy AVR .We implemented the randomisaiton successfully, producing groups similary at baseline, thereby reducing the risk of selection bias. The use of placebo ensure avoidance of performance and measurement bias. It may be thought that there is a potential of bias when patients report their pain scores and satisfaction subjectively. However as this is randomized placebo-controlled study, the subjectivity probably influences patients in both groups the same way due to practitioner and patient blinding, thereby avoid the risk of bias arising in the main findings. Another limitation of our study is that patients in both groups received a bolus of 0.75% ropivacaine at the end of the operation in line with the ethical requirements for this study. Furthermore the multimodal protocol also included metamizole a non-opioid analgesic administered to patients in both groups regularly. Therefore, we may be critisized that baseline analgesic requirement and pain were relatively low, such that a prominent effect of continuous wound infiltration is hard to demonstrate. However, as we did show a significant difference this concern did not materialize in our study. Thus we are confident that our findings are valid and reliable. An additional limitation of our study is the fact that the surgery was carried by the same surgical team which has extensive experience in right anterior minithoracotomy approach. Although this is rather a strength of the procedure performed, it needs to be taken into consideration as it creates a steeper learning curve, when carrying out future analysis or incorporation into clinical practice. We also recognize some limitations in the generalisability as ours is a single center study.Since our study, we have adopted the described pain relief protocol as a standard postoperative protocol for all our cardiac surgery patients when the procedure is performed with a minimally invasive technique. We use a wound catheter with PCA pump for all our minithoracotomy and ministernotomy AVRs, and also for our minithoracotomies for transapical TAVI procedures. The protocol is also made possible by our organisational structure which provides continuous monitoring of cardiac patients at least for the first 48 h, from ICU to HDU, where a nurse can check for pain levels hourly and administer an opioid bolus if needed.We found that wound infusion of local anesthetic by PCA pump significantly reduced opioid dose needed postoperatively. We have also shown that it is a feasible multimodal method of analgesia and it is in our opinion better suited to minimally invasive surgical techniques. Patient satisfaction with pain relief in our study was high. Therefore, we conclude that infusion of local anesthetic by PCA pump should be included in the multimodal pain control method following minimally invasive surgery.


Preoperative “Pain Intensity” (PI) on Numerical Rating Scale and postoperative PIs until day 7 were recorded. Patients' demographic and pre-/intra-/postoperative factors/conditions were recorded/analysed. The arms were homogeneous in terms of demographics. The mean preoperative PIs were similar (P=0.998), the mean sum PIs recorded during 10 postoperative intervals were comparable (P=0.939), and the trend/changes in pain relief were parallel (P=0.821) in all study arms. The incidences of preoperative moderate-severe pain in RCT, PMTA, and PCEM arms were 56.5%, 55.7%, and 56.7%, which after 24 hours considerably decreased to 13.1%, 10.6%, and 12.9%, respectively (P=0.578). The time span of endodontic procedures was statistically different; RCT = 69.73, PMTA = 35.37, and PCEM = 33.62 minutes (P < 0.001). Patients with greater preoperative pain, symptomatic apical periodontitis, or presence of PDL widening suffered more pain ; however, other pre-/intra-/postoperative factors/conditions were comparable. Pulpotomy with MTA/CEM and RCT demonstrate comparable and effective postoperative pain relief.This equivalence, randomized, clinical trial aimed to compare the postoperative pain of root canal therapy (RCT) with pulpotomy with mineral trioxide aggregate (PMTA) or calcium-enriched mixture (PCEM) in permanent mature teeth. In seven academic centers, 550 cariously exposed pulps were included and randomly allocated into PMTA ( Dental caries, as a chronic infectious disease, is a global health concern. The untreated caries is the most prevalent condition  evaluated for the entire “Global Burden of Disease”, as it remains the main cause for loss of all teeth . A systePain research has gradually expanded its prominence in all medical- and dental-related sciences. In endodontology, pain control in intra- and postoperative phases is a key aspect of clinical practice. Despite novel advancements in endodontology, up to 58% of patients have experienced postendodontic pain , 6, 7. HThe single available Cochrane review, appraising pulp management in carious permanent mature teeth with inflamed pulp, was not able to reach a conclusion and thus stated that further well-designed randomized controlled trials would be compulsory . RecentlAn ideal endodontic biomaterial for VPT must be biocompatible and antibacterial, able to provide a biological and bacterial-tight seal, and promote the regeneration of dentine-pulp complex . MineralA large noninferiority open-labelled clinical trial revealed that when general dentists treated cases with irreversible pulpitis, the pain-reducing effect of CEM pulpotomy (PCEM) was considerably more than that of RCT using hand instrumentation techniques . MoreoveIRCT20151226025695N3 and Registration Time 06 Feb., 2019) and approved by the Ethics Committee of Research Institute for Dental Sciences (IR.SBMU.RIDS.REC.1395.320) and Shahid Beheshti University of Medical Sciences (IR.SBMU.RETECH.REC.1397.1187). All experimental protocols were approved by RIDS (29-1395/09/23) and SBMU (10466-1396/04/26).The Iranian Ministry of Health and Medical Education (IMHME) commissioned this project. The trial has been managed by the Iranian Center for Endodontic Research (ICER) and Research Institute for Dental Sciences (RIDS) of Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran. The project was registered in the Iranian Registry of Clinical Trials  in Iran.The research grant was funded by the Deputy Minister of Research, IMHME. The funder had no role in the design/conduct of the trial and analysis of the data.The project was a multicenter, randomized, open-label, clinical trial.For this part, we hypothesised that pulpotomy with endodontic biomaterials (MTA or CEM cement) would be considered as an equivalent to root canal therapy, employing rotary instrumentation, in terms of postoperative pain relief.In this phase of the study, the primary outcome was to assess whether full pulpotomies with MTA or CEM cement decreased postoperative pain in permanent mature teeth with cariously exposed pulp compared with RCT.  Patients' demographics   Preoperative factors   Intraoperative factors   Postoperative factors Secondary outcomes were to assess probable associations between the following determinants and pain relief in cariously exposed mature teeth:It should be noted that the main endpoint of the second phase of trial would be the two-year radiographic outcomes.Volunteers were recruited from the pool of referred patients to seven postgraduate “Departments of Endodontics” in Iran. All patients had to adhere to inclusion and exclusion criteria.  Vital molar teeth   A history of pain, indicating irreversible pulpitis   Pulp exposure during caries removal   Patients in the range of 12 to 65 years of age  Patients who accepted to be available for recalls  Patients who approved and signed the written informed consent.Inclusion criteria were the following:  Nonvital/partially necrotic teeth (confirmed with primary examinations or diagnosed after access cavity preparation)  Teeth with continuous bleeding (after placement of a cotton pellet soaked in sodium hypochlorite for a maximum of 10 minutes)  Teeth that were not appropriate candidates for class I or II restorations and required complicated build-ups, crown lengthening, or prosthetic crowns  Teeth with localized/generalized periodontal diseases   Internal/external root resorption or detectable pulp chamber/canal calcification  Teeth with history of trauma  Immature teeth with open apices  Patients with systemic conditions that disturbed tissue healing process   Pregnant/nursing women  Physically/mentally disabled patients  Patients with poor oral hygiene  Immigrants, who were likely to leave the country during the subsequent two years  Patients younger than 12 years of age for the first molar treatment, 17 years of age for second molar treatment, and older than 65 years of age.Exclusion criteria were the following:Informed consent was obtained from all participants and from parents/legal guardians for patients under the age of 18 years.http://www.mcrct.ir) immediately before the commencement of the treatment. After recording the patient's demographics, eligible patients, using a computer-generated system and under the supervision of administrative staff, were automatically randomised into different study arms including PMTA, PCEM, and RCT. All the allocated patients received a unique patient identification code before starting the treatment. In the event of withdrawal from the study, the randomisation code was not reused. Patient blinding was not implemented; however, the assessors and analysers were blinded.Patients were allocated in the three study arms with simple randomisation. Randomisation was performed online . Then, the teeth were anaesthetized with 2% lidocaine and 1 : 80000 epinephrine . Upper and lower teeth were anaesthetized using infiltration and inferior alveolar nerve block techniques, respectively. Afterwards, cavity preparation and soft dentine removal were carried out using appropriate sterile high-speed diamond and low-speed large round burs, respectively. Subsequently, the tooth was isolated using a rubber dam and disinfected with 0.2% chlorhexidine.Complete pulpotomy was performed by means of a new sterile long cylindrical round-ended diamond bur  in a high-speed handpiece with copious water irrigation. To achieve hemostasis, a cotton pellet moistened with 0.2% chlorhexidine was placed into the pulp chamber for 5 min; and, if needed, it was replaced with a cotton pellet moistened with NaOCl 5.25% for 30 sec, or in cases of excessive hemorrhage, for 10 minutes. The pulp-covering agent  was prepared according to the manufacturer's instructions and then inserted into the pulp chamber. Using a dry sterile cotton pellet, the biomaterial was gently adapted on the blood clot-free pulpal wound and dentinal walls with a thickness of approximately 2–3 mm. Within the same session (after the placement of a moistened cotton pellet for 5 min) or further appointments, the cavity was permanently filled with Glass Ionomer  and light-cured resin-bonded dental composite , employing open/close sandwich technique.Similar to two other arms, teeth were anaesthetized and isolated, and pulpotomy was conducted. Then, working lengths were determined using Root ZX apex locator  and established 1 mm short of the apex employing parallel technique . A digital radiograph confirmed the working lengths.Root canal preparation was carried out using BioRaCe instruments . The endodontic motor  was adjusted at 600 rpm and 1.5 Ncm. Rotary files, with recommended sequences/motions, were employed in a crown-down manner according to the manufacturer's instructions. Root canals were irrigated with copious amounts of 5.25% NaOCl. Canal patency was confirmed with a #10 K-file during the procedures. Master apical file usually ranged to BR4 (35/0.04) or BR5 (40/0.04) for straight canals or BR4C (35/0.02) for curved canals. After radiographic confirmation of master cone, the canals were dried with sterile paper points . Using cold lateral condensation technique, root canals were filled/sealed with multiple gutta-percha cones  and AH-26 resin-based sealer . Within the same/further sessions, the cavity was permanently filled employing sandwich technique.α = 0.05, and β = 0.1 (power = 90%), the estimated sample size was 449.Sample size was calculated based on the two-year outcomes in previous studies , 29; thePostgraduate departments of endodontics in seven universities of medical sciences, located in five states of Iran, collaborated in this multigroup collaboration. Thirty-four postgraduate students (PGS) with similar experience/skills participated in the study. The selected PGSs attended a training workshop at ICER, which included the demonstration of the study protocol, hands-on training in RCT, and protocols on full pulpotomy treatment. Then, PGSs took/passed the final test and were considered qualified for the trial. The primary task of each PGS was to recruit nine patients and fulfill including/excluding criteria in each study arm. One endodontist from the academic staff of each department agreed to supervise all processes and activities, i.e., accordance of including/excluding criteria, standardisation of treatment, assessment of the outcomes, and recording of the data. The included centers were Azad Tehran (PGS = 6), Kerman (PGS = 5), Shahed (PGS = 2), Shahid Beheshti (PGS = 6), Shiraz (PGS = 6), Tabriz (PGS = 6), and Zahedan (PGS = 3) schools of dentistry.http://www.mcrct.ir. The database was inaccessible if the related data for each patient did not timely enter. At the end of study, coded data without the names of patients and treatment groups were extracted and analysed.Similar to previous studies , using aP < 0.05.The analysis of data was performed using SPSS software . The comparisons were considered significant if χ2) for age categories, sex, marital status, years of schooling, and distribution of treated teeth.A comparison of baseline demographic data was performed with one-way analysis of variance test (ANOVA) for age and the Pearson chi-squared test .Data for preoperative conditions including preoperative PIs, dental characteristics, preoperative pulp sensibility tests, and presence of apical periodontitis [PDL widening  or posiχ2, and FET.Data for intraoperative factors, i.e., type of pulp exposure, type of bleeding, irrigants usage for hemostasis, length of treatment, and number of treatment sessions, were analysed using Kruskal Wallis, ANOVA, t-test, ANOVA, χ2, and FET.Data for postoperative factors, including postoperative pulp sensibility tests and analgesic intake, were tested using independent The postoperative pain intensity, trend, distribution of severity, and survival in the study arms were compared using one-way/repeated measure ANOVA, ANCOVA, Kruskal Wallis, and Kaplan-Meier (log-rank) test.P > 0.05) (Five-hundred fifty participants that met the inclusion criteria agreed to be randomised in the study arms: 188 (34%) in PMTA, 194 (35%) in PCEM, and 168 (31%) in RCT . They we > 0.05) .P > 0.05) , the results of clinical/radiographic examinations (sensibility testing), and final clinical diagnosis, in all experimental arms, were similar ( > 0.05) .P < 0.001) and the treatment length of endodontic procedures (P < 0.001), all intraoperative conditions, i.e., type of pulpal exposure, nature of bleeding, achieving hemostasis, treatment length of restorative procedures, and number of treatment sessions, were similar in the three study arms (P > 0.05) (Except number of treatment visits ( > 0.05) .P > 0.05) , percussion tests, and analgesic intake, were comparable in all study arms ( > 0.05) .P < 0.001), the trend of PI scores amongst three study arms was similar during the study . There was no difference between arms for the quantity of pain relief (P=0.947) (P=0.002).Repeated measure ANOVA revealed that whilst PI changes, during post-operative 7 days, were statistically significant (P=0.947) . In addiP=0.496–0.942). In addition, the distribution of pain severities was comparable between the arms (P=0.056–0.993)  in different postoperative time intervals, Kruskal–Wallis test revealed that there were no significant differences between the study arms (6–0.993) . The mea6–0.993) .P=0.626, 0.197, 0.834, and 0.386, resp.). When dental characteristics were set as between-subjects factors, the test revealed that there were no statistical differences for the presence or absence of occlusal contact, occlusal attrition, and coronal restorations . When presence or absence of clinical apical periodontitis (positive response to percussion test), detection of PDL widening/lesion, and diagnosis of irreversible pulpitis were set as between-subjects factor, the test revealed that cases with apical periodontitis or PDL widening/lesion significantly suffered more pain  (P=0.782). In addition, severity of hemorrhage after pulp exposure, as well as hemostasis achievement after application of CHX, had no influence on postoperative PIs . Finally, other factors/conditions had no significant effect on postoperative PI in the study arms (P > 0.05).Repeated-measures ANOVA with postoperative PIs during the study as within-subjects factors, sex, marital status, age groups, and level of education as between-subjects factors showed that there were no significant effects  . HoweverPulpal pain, as a major component of oral health-related quality of life, is often the stimulus for patients to seek endodontic care . In addiBacterial invasion is often the cause for pulpal inflammation, which is considered as the cause of toothache. Therefore, the pulpal pain should be reduced if (i) the irritating factors are eliminated, (ii) the inflamed pulp is removed, and (iii) the surgical wound is protected by antibacterial BECs . PreviouIn all studied arms, mean preoperative PI scores were comparable , which were similarly decreased to approximately 1 and 0.5, one and seven days after treatments, respectively. In addition, the median time to pain-free status for all patients was 18–24 h. These results indicated that pulpotomy with BECs could be considered as effective as RCT in postendodontic pain relief; and, thus, the null hypothesis was accepted. These findings are supported with those of a systematic review which showed that moderate pretreatment root canal-associated pain severity dropped significantly within 1 day after treatment and continued to be lower to minimal levels in 7 days .In the present trial, patients with symptomatic apical periodontitis or detected PDL widening/lesion experienced more postoperative pain. In addition, the preoperative PIs were significantly correlated with postoperative PIs. Amongst several predictive factors for postendodontic pain, including patients' age/gender/level of education/marital status, tooth type/location, pulp/periapical status, types of intracanal dressings, systemic analgesic/corticosteroid/antibiotics intake, type of anaesthetics, number of treatment sessions, and different treatment procedures, the presence of preoperative pain is a major predictor of postoperative pain after endodontic treatments , 33, 34,Whilst mean baseline PI scores in this trial were classified as mild, approximately 20–22% of recruited cases reported severe preoperative pain. 24 hours after RCT (using rotary files) or VPTs, such preoperative pain dramatically decreased to roughly 1–3% of all patients, with no statistically significant difference between the arms. A previous noninferiority clinical trial on irreversible pulpitis demonstrated the effect of PCEM and one-visit RCT on pain reduction; however, when general dentists treated the teeth, pulpotomy arm significantly had faster/more pain relief than RCT using hand instrumentation techniques . A probaIn this trial, in addition to cases with carious pulp exposure, all cases with clinical signs of irreversible pulpitis were included. Based on the results of the cold test, 23.8% of enrolled patients were diagnosed with symptomatic irreversible pulpitis. However, postoperative pain relief between patients with or without initial diagnosis of symptomatic irreversible pulpitis was similar. It was assumed that irreversible pulpitis is a clinical term, which indicates that the painful vital inflamed pulp is incapable of healing and needs to be treated with RCT . CurrentAt the baseline, although approximately 70–73% of cases, in all study arms, responded to the cold test, almost all cases responded to EPT (98.8–100%). One week after full coronal pulpotomy, these responses to the cold test and EPT decreased to approximately 22–26% and 48–52%, respectively. Amputating the coronal dental pulp with rich subodontoblastic plexus of low-threshold myelinated A-delta sensory afferent fibers and replacing it with BEC, which is expected as an insulator, and maintaining the radicular pulp with high-threshold C sensory nerve endings, which are located far from coronal tooth surfaces , may expInability of paying for dental services while suffering from endodontic pain  and fearIn this trial, regardless of nature of bleeding, PGSs applied 0.2% chlorhexidine solution on all amputated pulps for 5 minutes to achieve hemostasis. However, in approximately 44–56% of cases, bleeding lasted longer than 5 minutes, which were effectively controlled with the application of full strength NaOCl for 30 seconds. In clinical practice, dentists and specifically pedodontists usually shift vital pulp therapy to pulpectomy or even tooth extraction if excessive hemorrhage is evident after pulp amputation or even at the site of pulp exposure . TherefoToothache, as the chief complain of patients, can be definitely treated through extraction or RCT . The latParticipants, without being excluded from the study, were permitted to take effective analgesics if needed postoperatively. The number of people who used analgesics, mean number of taken tablets/persons, and selected drugs were comparable in the study arms. The commonly taken analgesics were gelofen, ibuprofen, and acetaminophen, respectively. A recent systematic review revealed that administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and/or paracetamol was effective in the management of postendodontic pain .In this multicenter randomized controlled trial, the calculated sample size with 90% power was equal to be 449; yet 550 patients were enrolled. As the sample size increases, the minimum point of the power function moves toward one . An apprAlthough the trial was a multicenter study, it ran in a country with single race (white/Caucasian). It has been reported that chronic pain could be associated with race . TherefoOur study had two limitations. First, the trial had open-labelled design; and, due to the differences between treatment methods and materials, conducting a blinded study was not possible. Second, we did not assess the socioeconomic status of participants, whilst this factor might be associated with dental pain . HoweverA reported adverse side effect, after pulpotomy using calcium-silicate materials, was the potential of tooth discolouration . Grey diIn the management of symptomatic/asymptomatic mature permanent molar teeth with cariously exposed pulp, PMTA/PCEM and RCT demonstrated effective and comparable postoperative reduction of pain.


The study challenges the mechanism of sciatica pain and the role of IFN-γ in radicular pain development. Material and Methods. We performed clinical and immunoenzymatic assessment in a group of 27 patients with lumbar radicular pain due to disc herniations before and 3 months after surgery. Clinical status was assessed with the use of the Numeric Rating Scale (NRS), the Pain Rating Index and Pain Intensity Index of McGill Pain Questionnaire (SF-MPQ), the Oswestry Disability Index (ODI), and Beck Depression Inventory (BDI). The plasma concentrations of IFN-γ were ascertained by an immunoenzymatic method.  We investigated the influence of pain decrease after lumbar microdiscectomy on the interferon gamma  and after the procedure . These are moderate and positive correlations—the decrease in pain is correlated with the lower IFN-γ level. Additionally, there are significant correlations between the results of the PRI scale and the IFN-γ level. The PRI score before surgery correlates positively with IFN-γ after surgery , and the PRI score after surgery correlates positively with IFN before surgery  and after surgery . All correlations are moderate in severity—severe pain before surgery correlates with a higher level of IFN-γ after surgery and also higher IFN-γ before surgery. There were significant differences in the IFN-γ level before  and after  surgery in the groups of patients with and without nerve compression. In the group of patients with nerve compression, the level of IFN-γ before and after surgery was lower.  We observe significant correlations between the results of the pain in the back region assessment NRS back scale after the surgery with the level of IFN-γ. In the group of patients without significant nerve compression confirmed by MRI scans, the level of IFN-γ before and after surgery was higher than that in the group with nerve root compression. Less pain ratio after operation correlates with the level of IFN- It affects and regulates circulating macrophages in bone marrow and in disc tissue on a degenerated level [γ induces hyperexcitability of spinal dorsal horn neurons in vitro, indicating a potential role of proinflammatory cytokines in central sensitization. IFN-γ induces long-lasting depolarization of inhibitory loops thereby sensitizing the nociceptive ascending pathways [γ onto dorsal nerve roots was observed [γ onto dorsal nerve roots indicates direct action on ion channels [γ may induce strong allodynia effect on rats [γ lead to the disruption of the normal GABAergic tone in the rats' spinal dorsal horn which contributes to pain development [γ possibly induces neuronal dysfunction by the receptor-GluR1 complex leading to neuropathic pain [γ and TNF-α promoting neuroinflammation [γ released from macrophages in nucleus pulposus during herniation and extrusion could reach to dorsal horns and affects inhibitory interneurons crucial for nociception [γ contributes to pathogenesis in acute lumbar radicular pain following disc degenerative processes [γ in the area of nerve roots lasting several months may play an important role in the development of persistent pain and disability in patients with lumbar discopathy.Peripheral and central sensitization leads to a reduction of the pain threshold. It is also responsible for acute and chronic radicular pain as well as nerve irritation. Evidence indicates the proinflammatory cytokines' essential role in the regulation of nociceptive phenomenons –3. The kammation . There a therapy . Awarenerequired . Studiesed level . Some ened level . IFN-γ ipathways . A signiobserved . Rapid nchannels . A certa on rats . Prolongelopment . Additiohic pain , 14. Recammation . IFN-γ riception , 14, 16.γ serum levels with pain score scales combined with radiological scales such as Modic . In MRI scans, the grade of disc degeneration according to the Pfirrmann classification, the severity of facet joint disease according to the Weisshaupt scale, and Modic changes were evaluated. Disc rupture and nerve compression were confirmed according to radiological findings and intraoperative view. Divergent patients were excluded. An uninterrupted conservative treatment period oscillated between 8 weeks and 12 months before surgery and proved to be ineffective. Exclusion criteria were the use of corticosteroid therapy preceding 3 months before surgery, previous spine surgery, spinal stenosis, rheumatoid diseases, diabetes, cancer, psychiatric diseases, recent surgery, pregnancy, alcohol or drug abuse, and cigarette smoking. All included patients underwent the procedure by standard microdiscectomy and were operated by an experienced surgeon. All patients were assessed  before operation and followed up with a check-up 3 months after the operation. All patients were subjected to standard physical and neurological examination. The straight leg raising test and sensory, motor, and reflex deficits were assessed. Additionally, results in the Numeric Rating Scale (NRS) for the back and legs, the Oswestry Disability Index (ODI), the Pain Rating Index (PRI) and Present Pain Intensity (PPI) of Short-Form McGill Pain Questionnaire (SF-MPQ), and Beck Depression Inventory (BDI) just 1 day before the operation were collected.Indispensable to conducting the study, venous blood was collected in the morning and immediately centrifuged. Serum was stored at -80°C. A commercial enzyme-linked immunosorbent assay (ELISA) kit  was used for plasma samples. We followed the protocol recommended by the manufacturer. The ELISA Reader Victor  was used.U test for two independent samples. Rank correlation coefficients (rc and rg) were used to assess the effect size. The r-Spearman rank correlation coefficient was applied to assess the relationship between variables. The significance level α = 0.05 was assumed in the analyses.Statistical analyses were performed with the use of the IBM SPSS Statistics statistical package (version 24.0). The results are described as the mean, standard deviations, median values, and minimum and maximum values. Analysis of the differences between the level of interferon evaluated before and after the use of neurosurgical treatment was carried out with the use of the nonparametric Wilcoxon signed-rank test. For intergroup comparisons, we used the nonparametric Mann-Whitney The study was approved by the Local Human Research Ethics Committee. All participating patients were included following the signature of the written informed consent statement.M = 39.4; SD = 11.2), 10 women and 17 men. The vast majority of 18 people (66.7%) work in the physical profession, the rest in the mental profession. The average duration of pain lasted for M = 24.44 months (SD = 25.3) and ranged from 2 to 96 months —before the procedure, the mean value was 8.25 (SD = 5.18), after surgery, M = 9.61 (SD = 4.68); the effect size rc = 0.46 indicates a moderate relationship between IFN-γ level and surgery  than in the back area (rc = 0.44). The results in the ODI scale before and after the surgery differ significantly: Z = −3,600; p < 0.001; rc = 0.7. The results in the pain indexes before and after the surgery differ significantly: for PRI: Z = −3.254; p = 0.001; rc = 0.66 and for PPI: Z = −2.888; p = 0.004; rc = 0.57. The reduction in scale results after the procedure indicates a significant weakening of pain  and after the procedure . The decrease in pain scores after surgery is correlated with the relatively lower IFN-γ levels postoperatively. There are significant correlations between the results of the PRI scale and the IFN-γ level. The PRI score before surgery correlates positively with IFN-γ after surgery , and the PRI score after surgery correlates positively with IFN-γ before surgery  and after surgery . All correlations are moderate in severity. There are no significant relationships between the results of the ODI scale and the IFN-γ level. On the verge of significance is the low positive correlation between ODI scores before surgery and the IFN-γ level before surgery —high ODI results are accompanied by an increase in the IFN-γ level. There are no significant correlations between the Beck Depression Scale and the IFN-γ level  and without these symptoms  outlined a painful straight leg raising test, 18 patients (66.7%) reported reflex disorders, and 8 (29.6%) had paresis. In further analyses, it was checked whether the level of IFN-symptoms .γ level in the groups of patients with and without the problem of ruptured disc showed no statistically significant differences before surgery , as well as after surgery . Noteworthily, there is not only a higher average but also a much greater differentiation of the IFN-γ level in the group of patients with a ruptured disc than in the group with an unruptured disc. There were significant differences in the IFN-γ level before  and after  surgery in the groups of patients with and without nerve compression. In the group of patients with nerve compression, the level of IFN-γ before and after surgery was lower. There is a strong relationship between the nerve compression and the IFN-γ level. We identified 14 cases of Modic changes of type 2. The IFN-γ level before the procedure in patients with positive Modic changes differs significantly from patients with negative Modic changes—Z = −2.465; p = 0.014; rg = 0.64 , 2 with grade one, 8 with grade two, and 5 with grade three. The analyses did not show a statistically significant relationship between the IFN-rthritis .γ serum level in patients with lumbar radiculopathy treated with lumbar microdiscectomy, to examine correlations of IFN-γ with neurological symptoms, and to inspect relation with radiological signs and scales, before and after the procedure. A rare similar research has been performed on humans in this area. There are some limitations. The studies measuring the concentration of IFN-γ in the area of the nerve root or in the cerebrospinal fluid (CSF) were not performed yet so there is no evidence regarding the influence of IFN-γ on nerve roots or spinal cord pathways. There were ineffective efforts to evaluate cytokine concentrations in epidural space [γ on nerve roots in animals did not cause reduction in nerve conduction velocity [γ level in the cerebrospinal fluid (CSF) after pulsed radiofrequency treatment in patients with radicular pain [The study was carried out to investigate the role of the IFN-al space . Local avelocity . Better lar pain . The necDetermining the role of interferons in pain processes seems to be essential. Knowledge about pain processes concerning the molecular level seems to be a promising target for analgesic therapy, especially in the treatment of neuropathic pain. The animal model of a chronic constriction injury (CCI) of nerve structures causing neuropathic pain used to be used by many researchers –22. Sciaγ serum level changes in patients before and after surgery. Without additional causes of pain and comorbidities targeting IFN levels, the period of 3 months after surgery was chosen for the assessment to avoid abbreviations connected with healing of the postoperative wound. This is the time in which the patient can return to normal life and work after initial rehabilitation.The core of the above analysis seems to be the evaluation of the IFN-γ in patients after surgery increased significantly compared to the preoperative level with simultaneous reduction of pain. This is due to the fact that the surgery first removes the compression on the nerve root without affecting the ongoing process of neuroinflammation. Neuroinflammation decreases gradually after regression of the nerve root compression; some of the painful symptoms may persist after the surgery despite the end of the mechanical injury of the root. There is a question of whether the incision of the disc annulus and the exposure of the disc material can be a source of IFN-γ leading to its increase in serum [γ level before surgery and after surgery—reduction of pain after surgery correlates with the serum level of IFN-γ.The analysis shows that the level of IFN-in serum , 24, 25.γ level were found in individuals with an increased straight leg rising test symptom (≤45°) and less severe (>45°). It may be related to the fact that the straight leg raising test is a clinical expression of mechanical nerve compression, and, as a result, it is mostly an indicator of nociceptive pain [The analysis points at no significant differences in the IFN-ive pain .The level of interferon in the group of patients with a ruptured disc and without shows no significant differences both before and after the surgery. However, attention is drawn to the fact that in the group with the ruptured disc, there is a higher average of serum interferon level as well as its much greater variation. It may be related to the length of exposure of the disc material of the nucleus pulposus. It is worth remembering that an unruptured disc's nucleus pulposus is isolated from the circulatory system , 27, 28.γ level, despite the lack of significant nerve compression, may be the expression of central sensitization leading to hyperalgesia [According to Pfirrmann, we can distinguish a few variants of nerve root compromise by disc herniation. There are no contact, deviation, and nerve compression . There wralgesia .γ was detected in the group with the embedment of nucleus pulposus into subchondral bone in an animal model [γ in patients with positive Modic changes is significantly smaller than that in patients without confirmed Modic changes. The role of IFN-γ and Modic changes is still unclear.Modic changes are vertebral endplate and surrounding bone marrow changes in MRI , 31. Theal model . In our Elevated levels of many interleukins accompanied spondylolisthesis and disc herniation. Sutovsky et al. point at IFN gamma levels which were significantly higher in patients with spondylolisthesis and disc herniation in assessed intervertebral disc tissue compared to the control group. Levels of interferon gamma were significantly higher in the annulus fibrosus compartment comparing to nucleus pulposus levels (79.46 + −45.01 vs. 73.98 + −14.38). Results suggest the predominant expression of IFN gamma in the peripheral part of the degenerated disc. Close proximity between herniated annulus fibrosus and nerve roots could explain regional sensitization .γ which remains unchanged despite meaningful pain relief in patients suffering NP. Those findings suggest complex mechanisms underlying pain reduction during cord stimulation. Undoubtedly IFN-γ seems to be a key to understand pain processes [A study concerning neuropathic pain (NP) in the course of Failed Back Surgery Syndrome (FBSS) treated successfully with spinal cord stimulation (SCS) brings interesting results. Successful SCS did not influence elevated serum levels of IFN-rocesses .γ. In the group of patients without significant nerve compression confirmed by MRI investigation, the level of IFN-γ before and after surgery was higher than that in the group with nerve root compression. Because IFN-γ may be a target of therapy, further investigations are needed to establish the role of IFN-γ in raising and maintenance of sciatic pain.Clinical assessment of pain  after operation positively correlates with a lower level of IFN-


Spinal cord stimulation (SCS) is an effective method to treat neuropathic pain; however, it is challenging to compare different stimulation modalities in an individual patient, and thus, it is largely unknown which of the many available SCS modalities is most effective. Specifically, electrodes leading out through the skin would have to be consecutively connected to different, incompatible SCS devices and be tested over a time period of several weeks or even months. The risk of wound infections for such a study would be unacceptably high and blinding of the trial difficult. The PARS-trial seizes the capacity of a new type of wireless SCS device, which enables a blinded and systematic intra-patient comparison of different SCS modalities over extended time periods and without increasing wound infection rates.The PARS-trial is designed as a double-blinded, randomized, and placebo-controlled multi-center crossover study. It will compare the clinical effectiveness of the three most relevant SCS paradigms in individual patients. The trial will recruit 60 patients suffering from intractable neuropathic pain of the lower extremities, who have been considered for SCS therapy and were already implanted with a wireless SCS device prior to study participation. Over a time period of 35 days, patients will be treated consecutively with three different SCS paradigms  and placebo stimulation. Each SCS paradigm will be applied for 5 days with a washout period of 70 h between stimulation cycles. The primary endpoint of the study is the level of pain self-assessment on the visual analogue scale after 5 days of SCS.Secondary, exploratory endpoints include self-assessment of pain quality (as determined by painDETECT questionnaire), quality of life , anxiety perception , and physical restriction (as determined by the Oswestry Disability Index).Combining paresthesia-free SCS modalities with wireless SCS offers a unique opportunity for a blinded and systematic comparison of different SCS modalities in individual patients. This trial will advance our understanding of the clinical effectiveness of the most relevant SCS paradigms.DRKS00018929. Registered on 14 January 2020.German Clinical Trials Register, The online version contains supplementary material available at 10.1186/s13063-020-05013-7. Spinal cord stimulation (SCS) is an effective method to treat neuropathic pain of the lower extremity. A typical SCS device transmits electric current to the posterior columns of the spinal cord through a thin, epidural electrode. This electric current interferes with physiological pain transmission; however, the exact mechanisms of pain suppression are not fully understood. The epidural electrode is wired to an extension cable leading out through the patient’s skin, where it is connected to an implantable pulse generator (IPG) during SCS testing. To minimize the risk of local wound infection and transmission of wound infections to the epidural space, testing is usually constrained to a few days. If a patient confirms substantial pain relief, the extension wire and the IPG are implanted subcutaneously in a second surgery and can be operated by the patient via remote control.SCS has been used in the clinic for five decades; however, it is largely unknown which of the many available SCS modalities is most effective . This isThe PARS-trial seizes the capacity of a new type of wireless SCS device , which was approved for SCS in recent years . ConsistThis technological advance coincides with a second development, namely the development of paresthesia-free SCS modalities . These SCombining paresthesia-free SCS modalities with wireless SCS offers a unique opportunity for a blinded and systematic comparison of different SCS modalities in individual patients.The study aims to compare the clinical effectiveness of four SCS modalities in individual patients. SCS modalities include three prevalent paresthesia-free modalities  and placebo stimulation.This trial is a prospective multi-center, double-blinded, randomized, and placebo-controlled crossover trial.The PARS-trial will recruit patients at a total of 10 centers, including university hospitals and regional hospitals located throughout Germany. Given that participating centers estimated the numbers of enrolled patients to be roughly 2–3 patients/year, we opted for a higher number of hospitals to complete the study in approximately 2 years.The trial will recruit patients suffering from intractable neuropathic pain, who have been considered for SCS therapy according to the German guidelines and, prior to the study, were already implanted with a wireless SCS device . Inclusion criteria require placement of a single epidural electrode with the distal tip located between the 8th and the 12th thoracic vertebra. Patients with pain in the lower extremity are eligible for this trial. Pain distribution can be unilateral or bilateral. Patients with concomitant lower back pain are eligible too, as long as pain in the lower extremities predominates. Duration of pain history should be longer than 6 months and shorter than 5 years. This choice was based on a study by Kumar et al. [The trial will exclusively include adults (≥ 18 years of age) who provide written informed consent after (a) receiving detailed information pertaining to the trial , (b) having at least 24 h to consider trial participation, and (c) having no further questions at the time of consent. Only dedicated study physicians who have been trained and authorized by the principal investigator will recruit patients and/or gain informed consent. None of the physicians involved in the initial treatment, i.e., implantation of the wireless SCS device, will be involved in recruiting patients and/or gaining informed consent. Patients will be approached after implantation of a wireless SCS device by study physicians who will explain the study in detail. Should the patient consider study participation, he or she will be handed a detailed information sheet which has been reviewed and approved by the local IRB. All patients must be able to understand the nature and the extent of the trial.Exclusion criteria include coverage of pain area of less than 90% during intraoperative testing (using paresthesia-inducing stimulation). Patients suffering from other pain syndromes such as ischemic pain  and primary chronic pain will not be included in the trial. Exclusion criteria further include coagulopathy, pregnancy, neurodegenerative disease, lack of understanding of the trial, and any planned changes in existing pain medication for the duration of trial participation. We opted against exclusion criteria based on age limit but rather included neurodegenerative disease and lack of understanding of the trial as exclusion criteria to better reflect the biological age of patients.Patients can revoke their consent to participate in the trial at any time, in writing or verbally and without giving reasons for their decision. Patients who revoke their consent can decide whether their trial data should be included in the final analysis. Individual termination criteria with regard to trial participation include withdrawal of the patient’s consent to participate in the trial, severe wound infection leading to explantation of the SCS device, and any type of morbidity or patient discomfort leading to explantation of the stimulator.The study is planned as a fourfold crossover study using a Williams design. In a crossover design, patients are not randomly assigned to treatments, but rather treatment sequences are randomized. Such a crossover design avoids inter-patient variability and reduces the required sample size to power this trial. On the other hand, it increases the length of the intervention for each individual patient and thus, ultimately, might negatively influence patient compliance.Since some part of the SCS effect observed at early stages of therapy may be the result of a placebo effect, and some studies have reported placebo effects comparable to SCS effects , the stuEach patient is treated with four SCS modalities . All stimulation sequences are generated at the beginning of the trial, and each patient will be randomly assigned to one of 24 unique treatment sequences. An independent technician will program the SCS modalities as well as the order of the different stimulation modalities into the wireless SCS control hardware prior to the intervention.A randomization list was generated prior to trial initiation. The designated trial statistician had no access to the lists and was not involved in the generation of the randomization list. A randomization number (1–500) was randomly assigned to one of the 24 unique treatment sequences . This list was further divided into blocks of equal length so that each participating center would receive a list of randomized sequences and a matching number of sealed envelopes containing one treatment sequence per envelope .The following procedure is applied for allocation: patients are screened and enrolled at each center. Study personnel will remove sealed randomization envelopes from the investigator site file. Sealed randomization envelopes are then handed out to an independent technician who opens the randomization envelope and uses the treatment sequence to program the wireless SCS device.Study participants and physicians will be blinded to the order of the four stimulation modalities. The four different stimulation modalities will only be known to these two parties as programs 1–4. In coordination with the study center, patients will use the remote control of their SCS device to select the pre-set programs in consecutive order. There will be no contact with the independent technician for the duration of trial participation (35 days), and study personal must confirm double-blinding at the end of the study period. An emergency plan to unblind the treatment sequence was installed and can be enacted, e.g., in case the treatment sequence is required to replace a SCS device.All centers participating in the study will be proficient in the implantation of the wireless SCS device, i.e., have more than 1 year of experience implanting the device and/or have attended an implantation course offered by the Department of Neurosurgery at Heidelberg University Hospital. In addition, existing pain medication will remain unchanged for the duration of trial participation unless the patient’s condition requires changes in pain medication. Potential changes in pain medication will be recorded. Study participants are instructed to record each day, if there were any changes in medication. Any change of study medication within the intervention period will lead to study withdrawal.Seven days after implantation of the wireless SCS device, patients are contacted by the respective study center and asked to quantify pain on the visual analogue scale (VAS) and to complete the study questionnaires Table . PatientPrimary endpoint is the level of pain measured on the visual analogue scale (VAS) after 120 h of SCS. VAS is a globally used instrument where patients rank their pain on a scale from 0 to 100. “0” corresponds to the pain-free state and “100” to the maximum imaginable state of pain. VAS is the most prevalent endpoint for studies involving SCS. In addition to VAS rating, patients are asked to assess which SCS program was most beneficial to them during their final visit at day 36.Secondary endpoints include self-assessment through four validated questionnaires: pain quality as determined by painDETECT questionnaire (painDETECT), quality of life as determined by Quality of Life EQ-5D-5L questionnaire (EQ-5D-5L), anxiety perception as determined by the German version of the Hospital Anxiety and Depression Scale (HADS-D), and physical restriction as determined by the Oswestry Disability Index (ODI). All questionnaires are standardized and well established in SCS research –13.In addition, demographic and study-related data are collected by the respective study centers during the screening visit (immediately after consent/inclusion of study participants) and during the final visit, which coincides with the regular clinical follow-up on day 36 of the trial. Data include electrode position , medical history, potential complications related to SCS implantation, and total hours of stimulation per day.Routine implantation of the wireless SCS device occurs prior to the trial and as part of regular patient care (day 0). On days 1 and 2, patients are informed about the trial, and upon consent, inclusion and exclusion criteria are reviewed. Provided that all inclusion criteria and no exclusion criteria are met, an independent technician programs the previously randomized order of the four different SCS modes  into the SCS hardware. To patients, these four SCS modes are only known as programs 1, 2, 3, and 4. All patients are thoroughly instructed in the general handling of the SCS device. For a total of 7 days after implantation, SCS is switched off to wash out any potential effect caused by electrode placement during the preceding SCS surgery.After this first washout phase (day 7) and with SCS switched off, patients are contacted by the respective study center. Patients are asked to assess pain on the VAS and are requested to fill out four questionnaires . Time needed to complete the questionnaires is estimated at 1 h. Patients are instructed to activate the first stimulation mode immediately after completing the questionnaires. Specifically, patients are instructed to use each stimulation mode for 120 h and to stimulate at least 8 h per day. In addition, patients are asked to record daily stimulation durations in a patient journal, i.e., since it is not possible to record stimulation times with the wireless SCS device directly, patients are handed a diary after enrolment. This diary contains one page for every single day of the intervention. Study participants are instructed to record each time during the day when SCS was switched on and when SCS was switched off. If there are multiple periods of SCS during a day, patients are instructed to record stimulation times for each SCS period.After 120 h of stimulation with the first stimulation mode (day 12), patients are contacted by the respective study center and asked to assess pain on the VAS and to fill out the four questionnaires . After completing the questionnaires, patients are instructed to switch off stimulation. Now follows a washout phase of 70 h, during which stimulation remains switched off.After the washout phase (day 15) and with stimulation still switched off, patients are contacted by the respective study center and asked to assess pain on the VAS and to fill out the four questionnaires . Patients are then instructed to activate the second stimulation mode immediately after completing the questionnaires. This procedure  is repeated exactly until the patient has been subjected to all four SCS modalities.On day 36 , patients present for an outpatient appointment for regular clinical follow-up at the respective trial site, which coincides with the last study visit. Patients are asked once more to assess pain on the VAS and to fill out the four questionnaires  and are asked to assess which SCS program was most beneficial to them overall. An independent technician performs a final paresthesia-inducing test stimulation to confirm that the pain area is still covered by at least 90%. The patient then chooses the preferred stimulation mode.www.project-redcap.org). Completeness, validity, and plausibility of the data are checked by a data validation program. Questionnaires filled out by patients in paper form as part of the trial are forwarded by trial sites to the IMBI for data entry. Double data entry will be performed where applicable.Data management is carried out according to the Standard Operating Procedures (SOPs) of the Institute for Medical Biometry and Informatics (IMBI) Heidelberg. All demographic and trial-related data collected within the scope of this trial are entered by the respective trial sites into an electronic Case Report Form (eCRF) implemented in the Research Electronic Data Capture (REDCap™) system  Patients will be sensitized by study personnel and on several occasions to the fact that adherence to the study protocol is indispensable for study success. Date and time of each prospective study visit are explained to study participants and entered into a calendar which patients receive immediately after enrolment. (2) Study participants will be contacted via phone by study centers each time they have to assess stimulation effects and have to fill out questionnaires. During these phone calls, patients will be sensitized again to the fact that missing data might compromise the study. If a study participant cannot be reached within an agreed period of time, he or she will be made aware again during the first subsequent contact that a complete and precise procedure is essential for the success of the individual study. (3) A data validation plan was implemented. This plan generates automatic and instantaneous queries if data entry by study personnel is incomplete or implausible . (4) During the last study visit, study personnel screens each patient’s questionnaires to identify missing data. If missing patient data is identified and retrospective data collection does not compromise study results, patients are asked to provide missing data . Sample size calculation was done using PASS Vs. 16.03 and was based on previous work by Chow et al. [Sample size calculations are based on a previous SCS study protocol by Kriek et al. . Analogow et al. .p values of the corresponding statistical tests  and confidence intervals will be reported. The primary endpoint, pain perception on the VAS, will be evaluated using a linear mixed model with sequence, period, and treatment as fixed factors and patient as random factor. Statistical analysis will be done with SAS Vs. 9.4 or higher and the procedure proc mixed.All variables will be reported by tabulation of the measures of the empirical distributions. According to the scale levels of the variables, means, standard deviations, medians, and minimum and maximum or absolute and relative frequencies will be reported. Descriptive Since implantation of the wireless SCS device takes place independently and prior to study participation, rates of wound infection and technical failure are not affected by study participation.Monitoring is carried out by the Study Center of the German Surgical Society (SDGC) according to the SDGC’s SOPs and in compliance with the ICH-GCP guideline (E6). Monitoring focuses on patient safety and patient rights, on compliance with the study protocol as well as on data validity. All investigators must provide access to the SDGC’s independent monitors to study specific data and allow on-site visits before, during, and after study completion. Investigator site files are created and made available to the centers.The PARS-trial will compare the clinical effectiveness of the three most relevant SCS paradigms in individual patients. To our knowledge, the wireless SCS device employed in this study is the only device that can reproduce all relevant paresthesia-inducing and paresthesia-free SCS modalities. Our crossover study design seizes the advantage of wireless SCS, namely the possibility to test several different SCS modalities in one and the same patient, thus avoiding inter-patient variability and reducing the required sample size to power this trial.But even with this wireless SCS technology, it will be extremely difficult to compare paresthesia-inducing and paresthesia-free SCS modalities in a blinded fashion. The PARS-trial is thus restricted to paresthesia-free SCS modalities. In addition, patients are required to recharge their SCS device every 6 h, preventing patients from drawing conclusions about individual stimulation modalities based on different battery runtimes.To our knowledge, there is not enough systematic data to assess the optimal washout period. A recent review by Duarte et al.  identifiSince the wireless SCS device does not record stimulation duration, the PARS study protocol will rely on patients’ compliance to stimulate an average of 8 h a day and record stimulation times in a patient’s diary. An average of 8 h per day was chosen based on our previous experience with the wireless SCS system. We recently evaluated patients suffering from therapy-resistant neuropathic pain, who were implanted with a wireless SCS system at our institution . PatientFrom these results and from current practice, we also concluded that many patients who benefited from wireless SCS already benefited within 72 h, even though, in several cases, the full SCS benefit only materialized after several weeks. While extending each stimulation period in the abovementioned trial from 5 days to several weeks would be technically feasible, we would also anticipate a strong and negative effect on patient compliance. Altogether, we are convinced that 5 days of SCS per stimulation paradigm is the best trade-off between response times experienced in our pilot study and an appropriate length of the intervention period.In our experience, optimal electrode position  ranges from Th8 to Th12 for most patients. Thus, this range reflects a compromise between the need for a standardized electrode localization and the need to adapt epidural position to individual patients in order to achieve high (≥ 90%) pain coverage.An important feature in our study protocol is the washout period between each stimulation modality. There is little knowledge regarding optimal washout periods after initial SCS implantation and after SCS treatment. For our study protocol, we have thus chosen a conservative approach, i.e., 7 days of washout period after initial implantation and 3 days after each SCS cycle.Finally, during a recent evaluation of the wireless SCS system which was conducted at our institution , we had This manuscript is based on the current version of the study protocol . Recruitment of patients for the trial has started in April 2020. The clinical phase of the trial (last patient out) is expected to be completed in December 2022.Additional file 1. SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents.


The mean age of the six patients was 32.9 years . Patients were treated with this novel technique at our department and the functional outcomes were assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) scores during follow‐up. Information of the six patients including surgical data and pre/postoperative function scores were retrospectively analyzed using SPSS 19.0 statistical software.P < 0.05). The preoperative VAS pain scores were decreased from 5.8 ± 1.5 to 2.6 ± 1.4 at 24 months postoperative (P < 0.05) and slightly decreased to 2.0 ± 1.7 at 48 months postoperative (P < 0.05). No surgery‐related complications were observed in any of the patients.The average operation time between wire insertion and incision suture was 42.2 ± 11.5 min . The blood loss in all patients was all less than 50 ml each. The average fluoroscopy time was 25.7 ± 11.6 s . No wound‐related and other short‐term complications were recorded. Six patients who were included in our study were followed for an average period of 66.2 ± 4.7 months . There was no patient lost to follow up. Heel pain was observed to be greatly improved preoperatively in all of the six patients. All patients restored to normal activity of life after surgery. Radiological evidence of fusion was observed in five patients. The average fusion time of these five patients was 3.5 months . The remaining one failed to achieve fusion and the hardware removal was performed due to screw tail irritation. This patient was satisfied with the final outcomes subjectively after removal of hardware. The mean AOFAS scores at 24 months postoperative were 82.0 ± 7.0, which was greatly improved compared to preoperative (44.8 ± 10.7) (The novel technique can effectively relieve the heel pain, prompt functional recovery, decrease the incidence of complications, simplify the surgical procedure, and shorten the learning curve. Therefore, the technique is a feasible and worthwhile alternative in treating malunion after calcaneal fractures. However, this technique remains incapable of taking into consideration if there simultaneously exists lateral calcaneal bulge, varus or valgus deformity, and calcaneal shorteningin situ decompression of lateral calcaneal bulge and subtalar arthrodesis via a single incision. The technique maximally reduced the irritation to soft tissue and decreased the surgical difficulty. The aims of this study were: (i) to introduce a novel minimally invasive technique which has wider indications; (ii) to evaluate the feasibility of this novel method in treating malunion after calcaneal fractures; and (iii) to assess the effectiveness of the new technique.Calcaneal fractures can lead to malunion due to failure of the conservative treatment or surgery, which usually results in shortening and widening of calcaneus associated with severe varus or valgus deformity occasionallyFrom September 2010 to October 2011, six patients with delayed heel pain after conservative treatment of displaced intra‐articular calcaneal fractures were treated with our technique at our department. Inclusion criteria were as follows: (i) malunion after calcaneal fractures; (ii) Stephens and Sanders I or II type; and (iii) presented with intractable heel pain affecting normal life. Exclusion criteria were as follows: (i) concomitant with other severe limb dysfunction affecting prognosis; (ii) concomitant with severe underlying disease such as diabetes; and (iii) concomitant with severe calcaneal deformities such severe shortening, varus and valgus deformity, or loss of height. Malunion and broadening of the calcaneus can be seen on the axial view radiographs for all the six cases. The patients consisted of five males and one female. The mean age was 32.9 years . Among these patients, there was one case of type I and five cases of type II, according to the classification of Stephens and Sandersin situ decompression of the lateral bulged calcaneal wall and subtalar arthrodesis. Surgical technique was selected alone or in combination according to the causes of pain of each patient. In situ decompression of the bulged calcaneal wall was employed to release the irrigation of lateral calcaneal bulge on peroneal tendon sheath. Subtalar arthrodesis was employed to relieve pain secondary to post‐traumatic subtalar arthritis. Both minimally invasive techniques were performed through the same longitudinal single 3–4 cm incision.The surgeries consisted of two parts: The operative procedures were performed under epidural anesthesia. Patients were placed in the lateral decubitus position on a radiolucent operating table with the affected side upward. The location and range of lateral bulge on the lateral wall was determined under fluoroscopic visualization and marked.A 2 cm longitudinal incision was made at the lateral calcaneal bulge parallel to the Achilles tendon. Care should be taken to protect the sural nerve. A 2‐mm Kirschner wire was inserted as a guide wire into the site of 5–7 mm beneath the cortex of the later calcaneal bulge in parallel to the cortex Fig.  A,B. Thein situ decompression of lateral calcaneal bulge technique.Anesthesia and interoperative position was the same as In situ decompression and arthrodesis can be conducted simultaneously via the same incision if the incision was extended slightly proximally (approximately 1–2 cm). A guide wire was inserted into the subtalar joint along the superior border of the calcaneal tuberosity through the incision. Under the guidance of fluoroscopy, the guide wire was determined at the center of the subtalar joint  scores. Pain was evaluated according to a visual analog scale (VAS).The AOFAS score was employed to evaluate postoperative recovery of hind foot. The AOFAS score system mainly includes the three aspects of pain, function, and alignment. The maximum score of AOFAS score system is 100 points based on questionnaire and measurement .The VAS is a simple measurement method for pain intensity in clinical practice. Pain was evaluated using a visual analogue scale (VAS) ruler which has a scale from 0 (no pain) to 10 (unbearable pain). A higher score on the VAS ruler suggests a higher level of pain. The clinical evaluation is divided into excellent (0–2), good (3–5), fair (6–8), and poor (>8).All data were analyzed using SPSS 19.0 statistical software . The continuous variables are expressed as means ± standard deviation (SD), and significant differences were determined by Student's t‐test. A P‐value of <0.05 was considered as statistically significant.One patient received only minimally invasive decompression of lateral calcaneal bulge and five patients received decompression of lateral calcaneal bulge and subtalar arthrodesis via a single incision simultaneously. All patients completed the follow‐up with an average period of 66.2 ± 4.7 months  . The blood loss in all patients was all less than 50 ml each. The average fluoroscopy time was 25.7 ± 11.6 s .P < 0.05). Three of the four subjective indexes of AOFAS including at 24 months postoperative were all greatly improved compared to the preoperative values (Table P < 0.001) and slightly decreased from 2.6 ± 1.4 to 2.0 ± 1.7 at 48 months postoperative (T = 3.2 P < 0.05).Radiological evidence of fusion was observed in five patients. The average fusion time of these five patients was 3.6 ± 0.9 months . Preoperative heel pain was greatly improved in all patients after surgery. All patients restored to normal activity of life. The mean AOFAS scores at 24 months postoperative were 82.0 ± 7.0 , which was greatly improved compared to preoperative 44.8 ± 10.7)   in 11 patients who had irritation of lateral calcaneal bulge on peroneal tendon sheath and achieved satisfactory outcomes after long‐term follow‐up.in situ collapse of lateral bulge. This can effectively relieve the compression, protect the cortex, and restore the normal course of peroneus muscle. It did not damage the peroneal retinaculum and thus the incidence of dislocation was avoided. Meanwhile, it reduces or avoids the iliac bone grafting because subtalar fusion can be obtained with the harvested cancellous bone. In addition, it reduced the surgical trauma and the blood loss. More importantly, this technique did not dissect the soft tissue and thus maximally avoided the incidence of soft tissue‐related complications. Posterior ankle impingement second to calcaneal malunion is also considered to a very common reason for painIrritation of lateral calcaneal bulge on peroneal tendon sheath second to traumatic subtalar arthritis is a main cause of pain. Cabot lateral wall bulge after calcaneal fractures can lead to severe pain or even rupture of the tendons of peroneus longus and brevis musclesin situ subtalar arthrodesis and cannot deal with other associated deformitieset al. suggested that 50% fusion area can achieve satisfactory resultsMinimally invasive subtalar arthrodesis has become an increasingly popular topic. However, it is only available for P < 0.05). Subjectively, all patients achieved satisfactory results. During the two‐year follow‐up, one patient reported complete disappearance of pain and five patients reported occasional pain but all were greatly improved compared to preoperative state. These may be the main reasons for patients' satisfaction with the therapeutic results. Among the six patients, three had no limitation of daily activities and three had limited daily and recreational activities but crutches were not needed. Postoperative results regarding the maximum walking distance and walking surfaces were all greatly improved compared to preoperative state. Overall, the improvement of above four rewarding indexes may significantly improve the patients' satisfaction. In addition, the changes of VAS scores further confirmed this viewpoint.In this study, the mean AOFAS scores at 24 months postoperatively were 82.0 ± 7.0, which was greatly improved compared to preoperative scores (44.8 ± 10.7)  and the blood loss in all patients were all less than 50 ml each. The shortening of the operation time and reduction of blood loss may also contribute in avoiding the incidence of complications to some extentin situ decompression of lateral calcaneal bulge and subtalar arthrodesis can be conducted simultaneously via a single incision. However, it cannot effectively deal with severe calcaneal malunion, shortening, and decreased height of deformity. Thus, the procedure is still needed to be improved to extend the scope of application.This study has several limitations. Firstly, the insufficient sample size may lead to weakening of statistical characteristics. Ongoing clinical research with appropriate sample size is necessary to further confirm the efficiency of our technique. In addition, a well‐designed study should be held to investigate the relationship between various risk factors and postoperative outcomes which can further confirm the efficacy of our technique in the future. Furthermore, our surgical procedure extended the scope of application of minimally invasive technique, where Our technique is successful in treating malunion after calcaneal fractures, which can effectively relieve the heel pain, prompt functional recovery, and decrease the incidence of complications. In addition, it simplified the surgical procedure, shortened the learning curve, and thus seems to be a promising option in treating malunion after calcaneal fractures.Video S1 Surgical diagram 1:  a 2‐mm Kirschner wire was inserted as a guide wire into the site of 5–7mm beneath the cortex of the later calcaneal bulge in parallel to the cortex; (C) 8‐mm core drill was used to create the bone tunnel along the guide wire; (D) curette was used to scrape the residual cancellous bone beneath the lateral calcaneal bulge; (E) Kirschner wire was used to create several holes along the border of the lateral calcaneal bulge perpendicular to the cortex; (F) hammer was used to impact the bulge into the cavity.Video S2 Surgical diagram 2: (A) guide wire was inserted to determine the center of the subtalar joint; (B) core reamers with different diameters were used to expand the bone tunnel gradually; (C) curette was used to scrape the debris and cartilage through the tunnel as much as possible; (D) two cannulated screws were inserted along the guide wire to fix the subtalar joint.Click here for additional data file.