Inguinal hernia repairs are commonly performed procedures. The surgical techniques vary from open procedures to minimally invasive and robotic-assisted surgeries and include totally extra-peritoneal hernia repairs (TEP) and robotic transabdominal pre-peritoneal hernia repairs (rTAPP). So far, there is no randomized and blinded clinical trial comparing these two surgical approaches. Our objective is to investigate whether rTAPP is associated with a decreased postoperative level of pain.This is a prospective, single center, randomized and blinded clinical trial. Patients will receive either rTAPP or TEP for uni- or bilateral inguinal hernias. All patients and assessors of the study are blinded to the randomization. The perioperative setting is standardized, and all surgeons will perform both rTAPP and TEP to eliminate surgeons` bias. Primary endpoint is the assessment of pain while coughing 24 hours after surgery using the numeric rating scale (NRS). Secondary endpoints include the assessment of multiple pain and quality of life questionnaires at several defined times according to the study schedule. Furthermore, intra- and postoperative complications, duration until discharge, procedure time, duration of postoperative sick leave and the recurrence rate will be evaluated.ClinicalTrials.gov under the registry number NCT05216276.The trial has been registered at Trial comparing robotic and conventional minimal-invasive inguinal hernia repairRandomized and patient/assessor blinded trialEarly postoperative pain as primary outcome (24 hours)Secondary patient outcomes include pain and quality of life scores up to one yearFurther secondary outcomes: complications, costs, surgeon’s stress level Inguinal hernias are the most common type of hernias and the reported annual incidence varies from 13 to 34/10,000 13. The onThe applied surgical techniques for inguinal hernia repair have evolved over the past decades . For a l78Robotic-assisted hernia repair has previously been described as a “natural progression” . RoboticIn the literature, comparison of rTAPP and TEP shows controversial results. Some studies report lower pain scores and a lower incidence of complications for rTAPP compared to TEP 13. Other14We hypothesize that rTAPP will lead to a reduction of acute postoperative pain compared to TEP and that pain reduction will later translate into earlier recovery. We presume a 20% reduction of the numeric rating scale (NRS) while coughing 24 hours after surgery. Accordingly, the objective of the current randomized controlled trial is to investigate whether rTAPP is associated with a decreased level of pain shortly after surgery compared to conventional TEP.This is a prospective, single center, randomized and blinded clinical trial. The trial will be led by and conducted at the Clarunis, University Center for Gastrointestinal and Liver Diseases in the St. Clara Hospital in Basel, Switzerland.ClinicalTrials.gov under the registry number NCT05216276.This trial has been registered at Patients with a unilateral or bilateral inguinal hernia, older than 18 years of age and able to give their informed consent are included in the study. Exclusion criteria are recurrent hernias, previous open abdominal surgery at or below the umbilicus, liver disease defined by the presence of ascites, end-stage renal disease requiring dialysis, pregnancy, the inability to give informed consent, and the requirement of emergency surgery. Furthermore, patients with the need of an open surgery, due to their preference, the inability to undergo general anesthesia or to tolerate a pneumoperitoneum will not be included. A flowchart of participant recruitment, randomization and follow-up is shown in All patients seen during consultation for inguinal hernia will be registered. This primary assessment will be performed for every patient, including patients that withhold consent or fulfill any of the mentioned exclusion criteria, hereby ensuring a thorough documentation and a complete dataset.A numeric rating scale (NRS) of 4.37+/–1.66 at coughing 24 hours after surgery is assumed in the control group. This estimate takes two previous studies into consideration: the double-blinded randomized controlled trial by A. Mughal comparing TEP with and without peripheral nerve block  and the 2). This ensures that the groups will be similar regarding these important covariates. The randomization is performed by a case manager that is not involved in the treatment of the patients. The randomization is performed software-based using the REDCap randomization module. All patients and assessors of the study variables are blinded to the randomization. The surgeon is not blinded. The surgeon will not assess information for the endpoints. The exact surgery is not mentioned in the primary report before surgery nor in the surgery protocol given to the patient or to the postop personnel. The exact report is published only after 7 days. In addition, case manager, anesthesia-, OR-, wake-up-, ward-  personnel are informed about the blinded study. Given the fact that for rTAPP the incisions are made in a horizontal line at the level of the umbilicus and for TEP the incisions are made in a vertical line between the umbilicus and the symphysis, all patients will receive the same standardized opaque wound dressing, covering all potential incision sites. This ensures the blinding of the patients and the assessors of the study variables postoperatively. Patients will be unblinded 7 days after the surgery. Any violation of the blinding will be noted in the case reporting form.Patients are allocated to rTAPP or TEP by randomization. The randomization is performed as a block randomization and stratified for unilateral or bilateral hernias and for the body mass index , TME, mesh-rectopexy and TARUP. The operation scheduling will equally distribute rTAPP and TEP for each surgeon, to ensure an elimination of surgeons’ bias.Due to Swiss regulations, surgical treatment of a unilateral hernia is performed in an outpatient setting, whereas patients with bilateral hernias are hospitalized for at least one night. All patients will receive an intravenous antibiotic prophylaxis with 2 g of Cefazolin 30 minutes before the incision. The patients will receive a standardized general anesthesia with an endotracheal intubation, and intraoperative pain management will follow a standard based on fentanyl. Postoperatively, all patients will receive Celecoxib 200 mg twice a day for 5 days and Metamizole 500 mg 4 times a day for 7 days.The Xi da Vinci patient cart is placed on either side of the operating table with integrated table motion. The abdomen is insufflated with carbon dioxide using a Veress needle at Palmer’s point. The first 8 mm robotic port is placed above the umbilicus and the AirSeal® insufflator is connected hereto. After a brief laparoscopy, two further 8 mm robotic ports are placed on each side of the first port, with a distance of 6–8 cm. After placing the patient in a slight Trendelenburg position, the Xi robot is docked. The monopolar scissors are inserted in the right arm, the fenestrated bipolar grasper in the left arm. The center port holds the 30° endoscope. The peritoneum is incised 4–5 cm above the internal ring, from the median umbilical ligament in direction of the anterior superior iliac spine and gradually detached from the transversalis fascia. Medially the space of Retzius is entered and the Cooper ligament is exposed. Laterally the dissection is completed to the psoas muscle. The hernial sac is separated from the spermatic cord in males or the round ligament of the uterus in females and is then reduced. The peritoneum is then further dissected in cephalad direction for at least 5 cm to create adequate space for the mesh. The mesh with a size of at least 12 × 15 cm is positioned to cover the entire myopectineal orifice including the site of direct, indirect, and femoral hernias. The mesh is sutured to the Cooper ligament and in case of a larger medial hernia additionally to the ventral abdominal wall, using an absorbable Vicryl suture. The triangle of pain is meticulously spared. The initially opened peritoneum is readapted with an absorbable 3-0 V-Loc™. In the end, the ports are removed, the pneumoperitoneum is desufflated, and the skin is closed with a resorbable intracutaneous suture.The first incision is made at the umbilicus and access to the layer between the rectal muscle and the posterior lamina of the rectus sheath is gained. Here, a dissecting balloon is inserted to create a preperitoneal space under direct camera visualization and then a 12 mm port is placed. Two further 5 mm ports are installed along the median line below the umbilicus. The patient is placed in a slight Trendelenburg position and tilted towards the surgeon. Equivalently to the rTAPP procedure, the hernial sac is separated from the spermatic cord or the round ligament of the uterus and then reduced. The peritoneum is further dissected to create sufficient space for the mesh which is then inserted and positioned. The mesh is secured with glue or, in case of a M3 hernia according to the European Hernia Society (EHS) classification , with reThe primary endpoint is the assessment of pain while coughing 24 hours after surgery, measured on a numeric rating scale (NRS). The endpoint was determined considering that pain after inguinal hernia repair is a major issue as it may compromise the quality of life and acute postoperative pain may be seen as a surrogate for the development of chronic pain 2021.20Secondary endpoints include the analysis of the NRS score 2 hours, 7 and 30 days as well as 6 and 12 months postoperatively and the assessment of the inguinal pain questionnaire (sf-IPQ), the European Quality of Life 5 Dimension 5 Level questionnaire (EQ-5D-5L), the ICEpop CAPability measure for Older people (ICECAP-O), the Short-Form Six-Dimension (SF-6D), the 12-item Short Form Survey (SF-12) and the Carolina Comfort Scale (CCS) at multiple defined times within 1 year after the surgery. Furthermore, secondary endpoints include the evaluation of intra- and postoperative complications, according to the Clavien-Dindo classification and the Comprehensive Complication index (CCI), and the assessment of the recurrence rate 6 and 12 months postoperatively. The procedure time, duration until discharge, amount of intraoperative and postoperative pain medication, costs of the treatment, duration of the sick leave as well as the costs of the sick leave and the type of labor that can be conducted will be evaluated. Additionally, the ergonomics of the surgeons measured by the National Aeronautics and Space Administration Task Load Index (NASA TLX) and the Dutch Musculoskeletal questionnaire will be examined.Data is collected by a dedicated study nurse and the operating surgeon face-to-face or via telephone and online survey, after thorough explanation of the different scores and questionnaires according to the schedule displayed in Analysis will be performed on an intention-to-treat basis with all patients in the group to which they were allocated. Statistical analyses will be performed using IBM SPSS Statistics software , depicting continuous data as mean or median and categorical data as counts and percentage of total. The Mann-Whitney U-test will be used to compare ordinal data and the Fisher’s exact test for the analysis of nominal data. Multiple group comparisons of normally distributed continuous variables will be performed by analysis of variance (ANOVA). Pearson’s r-correlation will be used to correlate the primary and secondary outcomes with surgical experience as well as specific patient characteristics.


During stage II a subgroup of patients diagnosed with breast and prostate cancers with bone metastases, had the highest mean pain score improvement from baseline of 40% (unadjusted) and 33% (adjusted for rescue medication use). For all patients the most reported adverse events were mild or moderate drowsiness affecting 11 (44%) and 4 (6%) patients, respectively, and nausea and vomiting that affected 18 (72%) patients. The water-soluble cannabis-based medicine provided acceptable bioavailability for Δ9-THC/CBD, appeared safe and tolerable in advanced incurable cancers with uncontrolled pain with preliminary evidence of analgesic efficacy.This pilot study aimed to assess the safety, tolerability, pharmacokinetics and exploratory analgesic effect of a novel water-soluble oro-buccal nanoparticle spray of a cannabis-based medicine (MDCNS-01) in patients with advanced incurable malignancy with unrelieved pain from opioid analgesic. The study was a non-blinded single arm 2 stage study. Stage I was a single escalating dose (n = 5) [2.5 mg Δ9-THC and 2.5 mg CBD) versus a 3-fold escalated dose. Stage II was an up-titrated dose in patients with advanced cancers and intractable pain (n = 25). During Stage I with an increased cannabis-based medicine dose, maximum observed plasma concentrations of cannabinoids were dose dependant. The water-soluble formulation in the current study resulted in a higher median  systemic exposure of Δ9-THC than CBD (AUC from 2.5 mg each of Δ9-THC and CBD, was 1.71 ng mL.h Relief from chronic pain (cancer or non-cancer related) is a common condition cited by patients for the medical use of cannabis ,2. A recMost of the studies that have investigated cannabis for analgesia have concentrated on those with neuropathic pain. For example, low dose Δ9-THC 1.29%) as vaporized cannabis relieved central or peripheral neuropathic pain that was resistant to standard treatments compared to placebo . Studies9% as vapmax) after inhalation is associated with treatment limiting acute adverse effects and long-term damage can also occur from toxic chemicals associated with smoking or vaporizing ). Blood samples were collected at 0, 30, 60, 90, 120, 150, 180, 240, 360 min and 24 h after dose administration via indwelling cannula.Stage II was the up-titrated pilot study with 25 eligible participants diagnosed with advanced incurable cancer and uncontrolled pain as confirmed by the treating clinician while currently being treated with opioid analgesics. The stages of malignancy were verified but related on investigator assessment. Eligible participants were invited to participate over the three phases in a 30-day period. The three phases in Stage II were divided into a dose escalation phase over days 1 to 9; a treatment phase over days 10 to 15; and a follow-up phase over days 16 to 30. Prospective participants for all Stage II phases of this pilot study attended the Royal North Shore Hospital Medical Oncology unit for follow-up with the study investigator.Screening visits occurred −2 to 0 days prior to commencing administration of the THC/CBD water soluble nanoparticle oro-buccal spray . All participants commenced dose escalation; only 23 patients commenced the treatment phase; and 22 patients the follow-up phase of Stage II . Hence, This pilot clinical study was approved by the North Sydney Local Health District Human Research Ethics Committee and registered with the Australian New Zealand Clinical Trial Registry (number ACTRN12617001480370).During Stage I of the study patients administered one dose and then three doses only on consecutive days for the PK arm of the study. During Stage II of the dose escalation phase patients administered to the oral cavity (interchanging to the inside of either cheek) one, two or three actuations (1 actuation = 1 spray) every 4–8 hours (unless asleep) for six days. Patients that progressed to the treatment phase of Stage II administered one, two or three doses every 4–8 hours (1 dose = 2 sprays) unless asleep that was dependent on the safe and tolerable dose administered in the previous dose escalation phase of the study, as directed by the treating clinician.In the follow-up phase, all patients were observed for the next 15 days after treatment cessation. Subsequently, all patients who completed the study were provided with compassionate access to the ongoing cannabis-based medicine. Plasma samples whether during Stage I  or during Stage II were collected in-hospital prior to the first morning’s administration of the cannabis-based medicine on days 1, 4, 7, 10, 13, 16 and 30.™ (MDCNS-01) is a water-soluble submicron particle suspension light amber in color that also contains glycerol, peppermint oil flavor and a non-ionic oil-in-water solubilizer and emulsifying agent that is administered to the oro-buccal mucosa through a sealed pump action device that produced a fine mist spray. One actuation of the pump in this study administered 1.25 mg Δ9-THC and 1.25 mg CBD in a 150 μL volume.Medlab Clinical formulated the investigational product (MDCNB-01) which was manufactured by PCI Pharma Services  in a GMP accredited facility. PCI Pharma also conducted the filling of the vials containing the drug substance, labelling, and packaging and quality assurance release. The formulation MDCNB-01 was derived from plant material. The formulation consisted of 97.5% THC and CBD with the remaining 2.5% consisting of cannabidiolic acid, cannabigerol, cannabinol and cannabichromene. The Δ9-THC and CBD NanoCelle® (Sciex) system linked directly to the QTRAP5500 MS/MS detector and then processed in Watson LIMS™ (Thermo Scientific), where applicable. The calibration range was from 0.100 to 10.0 ng/mL for CBD, CBN, Δ9-THC and OHTHC and from 1.00 to 100 ng/mL for COOHTHC, using 100 μL of plasma and has a run time of approximately 8 minutes (as duplicate samples).The cannabinoid concentrations were measured using a validated assay that was co-developed with Medlab Clinical and that was conducted by Agilex Biolabs (previously known as CPR pharma services), a National Association of Testing Authorities (NATA) accredited facility based in Adelaide, Australia. Agilex Biolabs co-developed and validated the LC-MS/MS assay method. Blood samples from all eligible participants were assayed for Δ9-THC, CBN, CBD, 11-hydroxy-THC (OH-THC) and 11-nor-9-carboxy-THC (COOH-THC). Determination of cannabinoids CBD, CBN, Δ9-THC, THC metabolites 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (COOH-THC) and their respective deuterated Internal Standards were analysed in human plasma (100 μL) prepared using protein precipitation and solid phase extraction (using acidified acetonitrile and micro-elution plates). The analytes were separated by high performance liquid chromatography (HPLC) on a Phenomenex Kinetex Biphenyl column, and the eluates monitored by a QTRAP5500 tandem mass spectrometry (MS/MS) detector in negative MRM mode. The data were acquired an AnalystLaboratory assessments of the cannabinoids showed that there was no significant interference at the retention time of the internal standard (IS). Also, there was no significant interference at the retention time of the other analytes for each individual analyte injected at PS8 concentration without IS added . There were 5 repetitions performed on the same day. Coefficient of determination for curves run during validation had a linearity of >99%. Moreover, inter- and intra-assay precision had a mean coefficient of variation of approximately 3% (n = 18) and inter- and intra-assay accuracy had a mean % bias of approximately 3% (n = 18). Furthermore, there were no significant effects observed for any of the analytes in six individual lots plus in lipemic and hemolysed sources. The assay limit of detection for all metabolites was 0.1 ng/mL.Stage I if they: i) were aged greater than 18 years; ii) gave informed consent and agreed to comply with the study procedures (inlcuding a THC urine screen at baseline); iii) had been diagnosed with an advanced incurable malignancy; iv) were willing to abstain from using other cannabis-based medicines/recreational cannabis; v) agreed, where applicable, to use an effective form of birth control; vi) consented to baseline test for pregnancy; vii) consented to baseline tests for recent cannabis use; viii) agreed not to drive a car or other motor vehicle or operate any type of heavy machinery for 72 hours after the last dose of study medication.Patients were eligible for inclusion in Stage II if they: ix) reported experiencing moderate to severe pain; x) were currently receiving strong opioid analgesics for at least one week to relieve pain associated with incurable malignancy  and/or patient is on a low dose opioid regimen and still experiencing pain and is unable to increase the opioid dose due to poor tolerance as confirmed by the treating clinician; xi) reported pain severity greater than four on a 0–10 Numerical Rating Scale (NRS) assessment tool; xii) patients agreed to not partake in any other interventional clinical treatments other than the ones that the treating clinical team were already aware of for the duration of the study.”Patients were eligible to be included in excluded from participation if they met any of the following: i) demonstrated cognitive impairment or intellectual disability; ii) had a history of primary psychotic disorder, bipolar affective disorder, bipolar disorder with psychotic features, depressive disorder with psychotic features, borderline personality disorder, antisocial personality disorder, or a positive family history (first degree relative) of psychotic disorder or bipolar affective disorder; iii) had any history of allergic or hypersensitivity reaction to any herbal product, including cannabinoids; iv) reported a prior sensitivity reaction to an oro-buccal administered medicine or supplement ; v) had undergone radiotherapy to the mouth or oral cavity; vi) had significant intercurrent medical illnesses that the PI assessed to make them unsafe to be enrolled; especially a history of epilepsy (or a previous history of seizures), or clinically significant hepatic or renal impairment; vii) uncontrolled brain metastases; viii) pregnant or breast feeding; ix) had received epidural analgesia within 48 hours of the baseline assessment; x) had received radiotherapy within two weeks of the initial baseline assessment; xi) were currently receiving levodopa, sildenafil (or any other PDE5 inhibitors), anticonvulsants and/or cannabinoids, or ketamine; xii) participants were ineligible with a presentation of clinically significant liver dysfunction defined by 2.5 times higher abnormal liver function tests (in the absence of hepatic metastasis); and clinically significant kidney dysfunction defined by 1.5 times decreased glomerular filtration rate (GFR of < 50); and relevant to the full blood count a white blood cell count > 1,500 cells / μL and platelets > 100,000 cells / μL.Patients were Eligible participants were carefully instructed (provided with written information) and initially observed by nursing staff on how the cannabis-based medicine spray was to be administered to the oro-buccal area. Patients were also informed that they should not consume food, beverages (for at least 60 minutes before or after using the spray) or speak during the administration process of the cannabis-based medicine.All participants provided written informed consent and provided a urine sample at baseline for a qualitative THC screening prior to commencing participation into the study. There was no indication from baseline documented patient reports that enrolled participants had previously used recreational cannabis or had self-treated symptoms with cannabis.Participants were included if they were diagnosed with advanced incurable malignancy with controlled pain (Stage I) and intractable pain unrelieved by prescribed opioid analgesics for Stage II of the study.Primary Endpoints: consisted of a clinical assessment of safety and tolerability from recorded adverse events/serious adverse events; quality of life scores as measured with The European Organisation for Research and Treatment of Cancer Quality of Life for Cancer Patients Questionnaire (EORTC QLQ-C30-v3) ). All analyses were conducted in Stata MP V16 for Mac .Patient demographics and clinical characteristics are presented in Tables The patients completed the questionnaire at the induction visit and subsequent visits to the hospital and the treating clinician was blinded to this process. Given the complex presentation of the cohort of patients under investigation, we report the EORTC-QLQ-30 scores for those patients diagnosed with breast and prostate cancer with metastasis to the bone compared to those patients representing the rest of the cohort .There was an overall improvement from baseline for global health status; physical functioning; emotional functioning; cognitive functioning; fatigue; pain; dyspnoea and insomnia . The EORmax of 0.75 hours .The PK assessment of a single dose of 2.5 mg each of THC and CBD (2 sprays on Day 1) versus 7.5 mg each of Δ9-THC and CBD (six sprays on Day 2) was investigated for all participants in Stage I. The PK parameters calculated for Δ9-THC, CBD and Δ9-THC metabolites, 11-OH-THC and COOH-THC, are presented in 75 hours . Single 75 hours . The plaFor the Stage I part of this pilot clinical study, participants remained under clinical supervision in hospital for 48 hours to carefully assess safety and tolerability of the cannabis-based medicine administered and for blood sample collections. No within-participant comparisons were made between day 1 and day 2 pharmacokinetic parameters. Furthermore, during Stage I of this preliminary study, additional peaks in the plasma cannabinoid concentration-time graphs indicative of cannabis-based medicine swallowing were not observed.max, respectively  of Δ9-THC was 1.71 hr.ng/mL, 2.5-fold higher than the 0.65 hr.ng/mL for CBD  and a 1.8-, 2.7-, 1.8- and 1.9-fold higher Cectively . The sin for CBD . Further for CBD .In the Stage II of the pilot study plasma samples were also collected prior to the first morning administration of the cannabis-based medicine on days 1, 4, 7, 10, 13, 16 and 30.Adverse events were reported by patients daily to the clinical staff that were conducting the pilot clinical trial. All causally related AE that occurred during the treatment periods over 15 days (treatment-emergent adverse events) and their frequency are presented in In 9 of 24 patients (37.5%), reported emesis that was associated with nausea. In one patient nausea and vomiting were reported as persistent that subsided on interrupting the administration of the cannabis-based medicine. The last administered dose in this patient occurred on day 9 (first dose of the day) of the dose escalation phase of Stage II. In this patient the cannabis-based medicine was not tolerated at a dose frequency of 8 doses per day. The patient discontinued administering the cannabis-based medicine for the rest of the dose escalation period and the treatment phase.There were no serious adverse events  associated with the administration of the cannabis-based investigational medicine.The cohort in this study consisted of patients diagnosed with advanced incurable cancers with uncontrolled pain unresponsive to opioids prescribed for the management of pain. The most frequently prescribed rescue opioids were oxycodone, hydromorphone and morphine. As a group, patients diagnosed with metastatic breast and prostate cancer reported less prescribed rescue medications for the management of pain.mane and 150 mg nocte).Furthermore, other medications that were administered for pain management to participants enrolled in Stage II of the pilot study included pregabalin for 2 breast cancer patients (dose: 25 mg daily and 75 mg twice daily); one prostate cancer patient (dose: 25 mg daily); one CLL patient (dose: 75 mg daily); one patient with pancreatic cancer (dose: 25 mg daily); one ovarian cancer patient (dose: 50 mg twice daily); and one patient with NSCLC  all patThe median daily amounts of Δ9-THC of MDCNB-01 administered from day 1 to day 15 are presented in There was a reduction in pain overall for the study cohort of 12% by the end of the treatment phase . In the This study demonstrated that the administration of the investigative cannabis-based medicine (MDCNB-01) was generally safe and tolerated in a short-term exposure in a cohort of patients with advanced incurable cancers with controlled pain or intractable pain despite opioid treatment.Moreover, results from patient-reported outcome questionnaires suggested that patient functioning improved clinically for emotional functioning, fatigue, dyspnea, insomnia, and appetite loss, especially in those patients with improved pain management with the cannabis-based medicine, above what the maximal pain management was already providing.max and AUC(0-t) with half the Δ9-THC/CBD administered dose. The ethanol-based mouth spray (5.4 mg Δ9-THC/5.4 mg CBD) reported Cmax and AUC(0-t) of 1.48/0.39 ng/mL and 2.99/0.82 ng/mL.h, respectively [max and AUC(0-t) of 1.31/058 ng/mL and 1.71/0.65 ng/mL.h, respectively. Aviram and colleagues in their study [The water-soluble nanoparticle cannabis-based medicine formulation demonstrated acceptable pharmacokinetic behavior for cannabinoids consistent with safety and tolerability and preliminary analgesic benefit. There was a peak plasma concentration of less than an hour and adequate concentration to support multiple dosing every four-eight hours. An oromucosal mouth spray using 50% ethanol (and propylene glycol) does not seem to be as effective as the nanoparticle water-soluble spray. For example, comparing the PK data with that reported for the ethanol-based Δ9-THC/CBD mouth spray, MDCNB-01 achieved the same Cectively . With hair study  report tir study  that admIn the MDCNB-01 treatment phase, patients required an average of 6.4 mg/day THC for an effective dose, 2.7-fold lower than the 17.3 mg/day of Δ9-THC reported for an ethanol based (Δ9-THC/CBD) formulation, which achieved a similar improvement in NPRS score in an advanced cancer population . The cliFor oro-buccal sprays there is a risk that with high volumes administered that some of the volume will be swallowed prior to absorption, especially when the dose is high. Yet, the nanoparticle water-soluble delivery technology provided one peak consistent with mostly mucosal delivery, whereas a 50% ethanol mouth spray provided two peaks and inconsistent plasma levels , indicatThere is significant interest in the use of cannabis for the management of chronic cancer or non-cancer pain ,27 irresThere are clearly however, limitations to this study. The sample was small with an open label pilot design with no comparator that included only patients with advanced cancer, with intractable pain unrelieved by opioids. There was a substantial variation in eligible patient cancer diagnoses that produced a largely heterogenous study group. Furthermore, patients presented with multiple and overlapping types of pain. The missing data were not imputed, therefore our assessment of differences in quality of life may have some bias and should be interpreted with caution.In this cohort of patients with complex advanced cancers the adverse events encountered were similar to those commonly reported from other studies that have administered a cannabis-based medicine ; with thVarious clinical investigations with administered cannabis-based medicines via the gastrointestinal tract have reported limited tolerability and efficacy in a variety of indications . For smoNumerous animal –38 and hAlthough this study was not placebo controlled, the improvement in pain was consistent with a recent systematic and meta-analysis that concluded that cannabis-based medicines could probably achieve pain relief of 30% or greater compared with placebo. Interestingly in the metastatic breast and prostate cancer group cessation of MDCNB-01 use resulted in an average increase in the pain score of 13%.This report described a single ascending dose (Stage I and multiple ascending doses (Stage II) of a water-soluble Δ9-THC/CBD nanoparticle formulation administered to advanced cancer patients with intractable pain as a co-analgesic.There was an overall small improvement in average NPRS pain scores over the study treatment period from baseline. The significant improvement in average adjusted NPRS pain scores of 33% above that provided by standard analgesics was recorded for an eligible subgroup of participants with a diagnosis of metastatic breast and prostate cancers (only to bone). We acknowledge that in this preliminary study the secondary endpoint of analgesic clinical efficacy by the cannabis-based medicine will require further confirmatory data from a robust study, albeit the positive signal that was observed.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.S2 File(PDF)Click here for additional data file.S3 File(PDF)Click here for additional data file.


Results: There was no statistical dependence between the patient’s opinion about the medical institution and results of the effectiveness of analgesic treatments (p = 0.056). The highest percentage of patients satisfied with the received treatment were those who did not feel pain during ED discharge (94.12%), and the lowest were those who complained of severe pain during ED discharge (63.91%). The average mark for the functioning and organization of the emergency department was 7.44 (±2.04). Only 54 patients (29.83%) had taken pain medication before deciding to visit ED. Conclusions: No statistical dependency between the effect of the analgesic treatment and the patient’s opinion has been observed. The majority of patients with pain discomfort visit emergency departments without looking for consultation in other locations or without taking analgesics. In the considered institution, patients were satisfied with the analgesic treatment, staff performance, and with the organization of the department.Aim: The aim of the study was to analyze whether a patient’s opinion is related to the effect of analgesic treatment. Methods: The study was conducted using a survey questionnaire among adult patients admitted to the hospital emergency department in March 2021. The Numerical Rating Scale (NRS) was used to assess pain. Patients were asked to rate the intensity of pain during their stay in the emergency department in three situations: (1) at admission; (2) during the stay; and (3) upon discharge. The relationships between qualitative variables were assessed by the chi-squared test. Significance was set at  Although healthcare needs have developed from acute to chronic conditions in recent decades, the number of patients admitted to emergency departments (EDs) has increased worldwide, both in public and private healthcare systems ,2. EmergThe aim of the study was to answer the question of whether patients’ opinions about the emergency department were related to the effects of pain treatments. The second goal was to investigate the intensity of pain and whether the patients had used pain medication before arriving at the ED.Mild (NRS 1–3);Moderate (NRS 4–6);Strong (NRS 7–10) .A study using a questionnaire was conducted among patients who used the medical services of one multidisciplinary hospital emergency department in March 2021 in Poland. The Numerical Rating Scale (NRS) was used to assess pain. Patients rated their pain from 0 to 10: zero represented ‘no pain at all’, whereas the upper limit represented ‘the worst pain ever possible’ . AccordiPatients were asked to rate the intensity of pain during their stay in the emergency department in 3 situations: (1) at admission; (2) during the stay; and (3) upon discharge.The study was conducted in a contact manner, maintaining voluntary anonymity, as well as with respect for the patient’s rights, including maintaining medical secrecy. Patients gave oral informed consent for their involvement in the study. The inclusion criteria for the study included the following factors: (a) using health services in the ED in March 2021; (b) the patient’s state of health that allowed them to take part in the study; (c) full logical contact of the patient and orientation as to the place, time and person; (d) ensuring that the patient was not under the influence of narcotics or designer drugs; and (e) patients aged >18 years. The following data demographics were entered into the database: age, gender, place of residence, and level of education. A total of 218 patients participated in the study, but due to the lack of proper completion of the questionnaire, 12 questionnaires were excluded from the study.p < 0.05.A group of 206 people was involved in the creation of the database. Statistical analysis was performed using the STATISTICA program, version 13.1 . For the analysis of sociodemographic characteristics, evaluations of pain intensity were used as standard descriptive statistics . The qualitative variables were expressed as frequencies (N) and percentages (%). The relationships between qualitative variables were assessed with the chi-squared test. Significance was set at n = 78), some in a smaller city 29.6% (n = 61). Other respondents (32.5%) declared that they lived in villages (n = 67). All respondents were adults  and 106 males (51.5%). Most of the 206 participants live in a big city that has more than 150,000 citizens. In an examined group, some people declared that they lived in a big city 37.9% (e adults .n = 64); 24.3% had achieved a higher level of education (n = 50). People who had completed vocational education represented 20.9% (n = 43). The two last possibilities were primary education—this option was chosen by 14.1% (n = 29)—and medical education, which was selected by 9.7% (n = 20).The most numerous group consisted of people who had achieved a secondary education—31.1% . When pain intensity was next checked when during the patient’s stay in ED, the average value was 4.4 . The last check of the rate of pain was during discharge. The average rating was the lowest and was 2.89   .p = 0.056).In the end, the pain rating and satisfaction with the medical service were compared. At the time of discharge, 95% of patients who did not feel pain were satisfied with the provided medical service. There were slightly fewer people who experienced mild pain—92.1%. In the group of people declaring moderate pain, 80% of people were satisfied, and 63.9% of people with severe pain. There was no statistical dependence between the rate of pain and satisfaction with provided medical service (n = 46); stomach/abdomen/genital organs (n = 29); many-body localization (n = 22)  .n = 179) of patients presented to the emergency department because of pain, which is a similar result as compared with other studies. [In this study, 86.89% . Similar results were obtained by van Zanden et al. where patients included in the study expressed relatively high patient satisfaction with pain treatment—7.83 on a 0–10 scale [When it came to patients’ satisfaction with receiving medical services, the majority of respondents were 86.41% n = 8. SimilaAlthough there was a decrease in patients’ satisfaction with the services provided in the hospital emergency department with higher pain intensity , statistical significance was not demonstrated. Patients in emergency departments had very high expectations for pain relief, often much higher than people with postoperative pain .n = 54) of patients had taken pain medication before arriving at the hospital emergency room. This result is similar to that of Tasdemir et al., where 30.1% of patients had taken pain medications before arriving on ED. However, in a study by Tasdemir et al., an additional 21.3% had used alternative pain treatments before arriving at the ED [Only 29.83% (t the ED . The caut the ED . MoreoveThe main limitations of this study were that it concerned only one hospital emergency department as well as the period of data collection, i.e., one month a year. Moreover, the small sample may limit the generalizability of the findings. Additionally, research was carried out during the COVID-19 pandemic, which considerably influenced disease and social-demographic information. Key limitations were the criteria of inclusion to the study and selected method of examination—survey/questionnaire in the paper form.No statistical dependency between the results of analgesic treatments and the patient’s opinion has been observed. The majority of patients with pain discomfort visit emergency departments without looking for consultation in other locations or without taking analgesics. In the considered institution, patients were satisfied with the analgesic treatment, staff performance, and with the organization of the department. A low percentage of patients had taken pain medication before arriving at the hospital’s emergency department, a phenomenon of which the causes require further investigation. In addition, patient education in this regard could contribute to reducing the occupancy rate in hospital emergency departments.


The consideration of regional analgesia (RA) in below-knee surgeries is always a controversial topic due to the fear of masking symptoms of developing compartment syndrome (CS) in the postoperative period. Compartment syndrome (CS) has been found frequently in below-knee surgeries, particularly among tibial diaphyseal fractures. Like any other surgery, below-knee surgeries have significant postoperative pain that requires effective postoperative analgesia protocol. The analgesia quality makes a big difference when compared with or without RA. Also, the presence or absence of RA cannot prevent or promote the development of CS. Therefore, patients should not be deprived of their right to remain pain-free in the postoperative period by compromising the analgesia protocol.The pain out of proportion to the surgery or injury is a typical symptom of developing CS, which can cause increased analgesic demands postoperatively. Timely diagnosis and treatment of CS require vigilant postoperative monitoring of the warning signs by trained staff. Avoiding RA for fear of presumed masking of symptoms and delaying CS diagnosis may not be a solution instead of choosing an appropriate RA with regular postoperative monitoring for such warning symptoms. The high-volume proximal adductor canal (Hi-PAC) block has been described as a procedure-specific and motor-sparing RA technique appropriate for below-knee surgeries.In this prospective study, we evaluated the analgesic efficacy of the Hi-PAC block in below-knee surgeries. We also observed the effect of the Hi-PAC block, due to proximal and distal drug distribution, on masking the symptoms of the developing CS during postoperative monitoring.We found the Hi-PAC block to be a safer and more effective RA alternative for below-knee surgeries with an added motor-sparing benefit that facilitated early mobility and discharge. Its property of not interfering with postoperative surveillance to detect the symptoms of CS and intervene in time helps deal with the anxiety of CS in below-knee surgeries. Perioperative pain management for patients undergoing below-knee surgeries is challenging due to the concerns about the postoperative development of acute compartment syndrome (ACS). ACS is a true orthopedic/traumatic/surgical emergency that can lead to ischemia and eventual necrosis if left untreated, resulting in significant morbidity and mortality. The incidence of ACS is 1%-10% of all leg fractures, of which 75% of cases are associated with long bone fractures , followed by distal radial fractures (18%) . It can Fear or anxiety of ACS deprives patients of the optimal analgesic options and exposes them to severe postoperative pain, resulting in an unsatisfactory hospital stay. Dependency on systemic analgesics alone often fails to meet escalating postoperative demands resulting in inadequate analgesia or oligoanalgesia. A comprehensive team approach is required to manage such a preventable and treatable situation. It requires identifying high-risk patients or surgeries prone to developing ACS, providing the most suitable analgesic regimen, and periodic vigilant monitoring of the signs and symptoms of impending compartment syndrome (CS) postoperatively by trained personnel -11.The application of regional analgesia/anesthesia (RA) in below-knee surgery is contentious due to the belief that it can mask ACS symptoms and put the patient at an unacceptably high risk of serious morbidity. However, evidence for such an assumption is lacking. We believe that RA neither masks the clinical symptoms of impending CS nor prevents ACS development. The development of ACS can be inevitable under favorable circumstances regardless of the presence or absence of RA. Therefore, the mere fear of preventable and treatable conditions such as ACS should not deprive patients of their right to remain pain-free with effective and complete postoperative pain management.An ideal RA technique for below-knee surgeries should provide effective analgesia without masking the symptoms of the developing CS and facilitate early mobilization and discharge. The high-volume proximal adductor canal (Hi-PAC) block is one such suitable RA technique described for below-knee surgeries -14. In oWe aimed to observe the analgesic efficacy of the Hi-PAC block along with its technical ease of administration, the clinical effect due to drug distribution pattern, and possible interference during daily postoperative evaluations to detect the symptoms of CS in patients included in this prospective study. We hypothesized that the Hi-PAC block would provide the desired procedure-specific and motor-sparing postoperative analgesia without masking the symptoms of the impending CS. We propose a new paradigm and an alternative RA technique to ensure safer and more efficient postoperative analgesia in below-knee surgeries.This prospective study included 15 patients of either sex with the American Society of Anesthesiologists (ASA) grades I and II who underwent lower extremity orthopedic surgeries below the knee joint under neuraxial anesthesia. We conducted this study from September 2021 to October 2021 with our hospital institutional review board (IRB) approval (reference number IRB/GH/Anaesthesia/008/2021/004). All study patients provided informed consent for anonymous data recording and sharing concerning this study.Patient preparationPreoperatively, all patients were premedicated with intravenous pantoprazole 40 mg, ramosetron 0.3 mg, and midazolam 2 mg. The proposed surgery was performed under neuraxial blockade, either spinal or combined spinal-epidural under tourniquet control. Intraoperatively, paracetamol 1 gm, ketorolac 30 mg, and dexamethasone 8 mg were administered intravenously as MMA protocol. The remainder of the intraoperative course of all patients was uneventful, without any need for change in anesthesia or analgesia protocol.Postoperatively, all patients were monitored in the recovery room and periodically assessed for the recovery of motor movements. In possible cases, preprocedural scans of the femoral nerve (FN) and popliteal SCN were performed to compare sonoanatomy before and after the block. After confirming motor recovery (active toe movements) prior to sensory , the Hi-PAC block was administered using 40 mL of local anesthetic (LA) solution (0.1% ropivacaine + dexamethasone 8 mg).Ultrasound-guided Hi-PAC blockA high-frequency linear ultrasound probe  was held transversely over the midthigh with the patient lying supine Figure . InitialThirty minutes after the Hi-PAC block, all patients’ toe movements were reevaluated. They were monitored in the recovery room till complete regression of spinal level and attaining discharge criteria. A postoperative MMA protocol was followed: oral paracetamol 1 gm four times a day, aceclofenac 100 mg twice a day, and pregabalin 75 mg at bedtime. Postoperative pain scores were recorded before and after the block and periodically for up to 24 hours using a visual analog scale (VAS) of 0-10 (0 = no pain and 10 = worst pain imaginable). Focused postoperative evaluations to screen the signs and symptoms of ACS were performed daily till the discharge of the patient. All patients were discharged on the fifth postoperative day with a mean pain score of 2/10 on VAS without any requirement of rescue analgesia or opioids.Primary and secondary outcomesThe primary outcome of this study was to determine the analgesic efficacy of the Hi-PAC block in providing postoperative analgesia for below-knee surgeries. The secondary outcomes included determining the duration to administer the block, determining the extent of the proximal drug distribution to check the involvement of additional neural components , confirming distal drug distribution around the SCN in the popliteal fossa, determining the distance of the drug spread around SCN from the popliteal crease, and calculating the total duration of the analgesia.Outcome measurementThe measured outcomes included the demographics of the patients, type of neuraxial anesthesia, duration of surgery, vital parameters, time to regain toe movement, time to administer block, proximal and distal drug distribution after block, pain scores (at rest and after squeezing leg muscles) at regular intervals for the first 24 hours, total analgesic duration, presence of any signs of compartment syndrome and complications till discharge.Data were encoded and recorded in an MS Excel spreadsheet program . Statistical analysis was performed using SPSS version 23 . Descriptive statistics were generated using means/standard deviations (SD) for continuous variables and frequencies and percentages for categorical variables Table . Data weWe found no significant change in vital parameters before and after the Hi-PAC block Figure . The meaThe mean time to regain toe movements after the neuraxial block was 293.33 ± 75.96 minutes. The mean time to administer the Hi-PAC block was 5.13 ± 1.35 minutes. Post-block scanning distally into the popliteal region confirmed drug spread around the popliteal SCN in 11 patients with a mean distance from the popliteal crease of 8.467 ± 4.51 cm. However, due to an above-knee slab/cast, distal scanning could not be performed in three out of 15 patients. Post-block scanning proximally into the distal femoral triangle revealed drug spread around SN in 15 (100%) and nerve to vastus medialis (NVM) in 14 (93.3%) patients. However, none of the patients had drug distribution around the FN in proximal FT. The total duration of analgesia in most of the patients (12 out of 15) was >24 hours  with motor-sparing advantage for sufficient duration (>24 hours) with the Hi-PAC block in below-knee surgeries. It helped reduce the need for rescue analgesics and subsequent opioid consumption postoperatively. Incorporating this novel RA technique into the postoperative pain management strategy resulted in increased patient compliance and satisfaction. Before deciding on an appropriate target-specific RA strategy, functional anatomy should always be considered. Hence, we followed the identify-select-combine approach : identifThe innervation of the leg below the knee is not as complex as that of the knee joint. It involves the major contribution from the SCN and a minor contribution from the SN  . The sinThe pain caused by the impending CS is fundamentally disproportionate to the injury or surgery. It can be considered an earlier marker of ACS than the classic “six Ps”  . Such a In our study, such excruciating pain out of proportion to the surgical dissection provided timely warning signals indicating the development of increased compartment pressure. Thus, despite a well-functioning regional block, such ACS-pro conditions were promptly diagnosed and addressed simultaneously. This situation led us to recognize the importance of postoperative monitoring of the developing CS, particularly in high-risk patients/surgeries, without compromising effective postoperative analgesia. Therefore, regular postoperative monitoring of the clinical signs of ACS by trained personnel should be mandatory in below-knee surgeries. Selective sensory RA techniques with low concentrated LA are preferred to facilitate such monitoring. However, such postoperative monitoring should not depend on whether the RA technique is included or excluded in the MMA regimen.In addition to postoperative monitoring, preoperative patient preparation and identification of possible risk factors are essential. The timing of surgery also plays an important role in preventing the development of postoperative ACS. Our surgical team thoroughly evaluated all study patients before posting them for surgery. Factors that caused the initial postponement of the surgery included significant edema over the affected area, blistering, the absence of skin wrinkling, or the inability to fold the skin over the affected area. These visual findings suggested increased compartment pressure due to injury and edema formation, which required preoperative monitoring in order to assess the further rise in compartment pressure or the need for emergency fasciotomy. Therefore, thorough preoperative and postoperative evaluations with the early suspicion of the disease help invoke an immediate response and prevent the future possibility of ACS .The use of RA in below-knee surgeries always creates a “to give or not to give” dilemma that supports both sides of the coin Figure . It may Every patient has the right to receive adequate, effective, and complete analgesia. As pain specialists, we also have a responsibility to keep our patients pain-free by selecting the most appropriate and safest analgesic protocol that must include RA as an essential ingredient. Incorporating the RA technique as an adjunct to MMA in any surgery has been proven multiple times to significantly reduce analgesic/opioid consumption and ultimately improve patient satisfaction by promoting enhanced recovery, early mobilization, and early discharge -28. SuchThis study was conducted as a pilot project for future comparative studies. The strengths of this study include recording the analgesic efficacy and motor-sparing effect of the Hi-PAC block for the first 24 hours, along with subsequent vigilant monitoring of the signs and symptoms of the developing compartment syndrome until discharge of all patients. The limitations include small sample size, monocentric nature, lack of a control group, and scope for various biases (selection and observation).In conclusion, the Hi-PAC block can provide effective postoperative analgesia without compromising the motor strength of the leg muscles and without masking the clinical symptoms of ACS during the periodic assessment of the patient. We believe that the Hi-PAC block can be an appropriate RA option to deal with ACS concerns/fear (ACS anxiety) associated with below-knee surgeries. Apart from all clinical advantages of the Hi-PAC block, it is a relatively easier block to learn (simple identification landmarks), administer , overcome difficulties such as the above-knee cast, and teach to trainee regional anesthetists. This novel RA technique needs to be further explored with prospective multicenter clinical trials of larger sample sizes to substantiate the results better. In addition, it requires radiographic or cadaver dye studies to correlate clinical outcomes with neural component involvement.


Post-traumatic trigeminal neuropathic pain (PTTNp) is a painful condition that may result from injury to the sensory division of the trigeminal nerve. Treatment of this condition is challenging and consensus on treatment to resolve neuropathic pain has yet to be standardized. Equally as challenging is the identification of surgical outcome variables to guide surgical treatment of PTTNp. This is partly due to the variability in pain characteristics, severity of nerve injury, location, and duration from injury to surgery. In those with neuropathic pain prior to microsurgical intervention, the incidence of neuropathic pain after microsurgical intervention is 67%. It is unclear why nerve repair surgery is effective in resolving or decreasing neuropathic pain in some patients, whereas it has no effect on pain relief in others. Psychological, medical, and age-related factors have been identified as risk factors for developing chronic post-surgical pain due to post-traumatic neuropathic pain. Two factors: injury to surgery time and preoperative visual analog scale score have recently been identified as variables that influence surgical outcomes in the treatment of PTTNp. Iatrogenic injury to the trigeminal nerve may occur following elective dental or oral and maxillofacial surgery procedures. The branches of the trigeminal nerve usually affected are the inferior alveolar nerve (IAN) and the lingual nerve (LN) , 2. ThesFollowing injury or insult to the trigeminal nerve, some patients experience post-traumatic trigeminal neuropathic pain (PTTNp). PTTNp is a painful condition characterized by allodynia, hyperpathia, and/or hyperalgesia. Allodynia is a painful response to a normally nonpainful stimuli, hyperpathia is a complex painful response to repetitive nonpainful stimulus, and hyperalgesia is a lowered pain threshold to a painful stimulus. The cause of PTTNp is still unknown but animal studies have implicated various biological processes such as inflammation, enhanced neuropeptide-mediated pain signal transmission, endothelial receptor activity, and glial cell dysfunction causing trigeminal hyperexcitability . PTTNp mA number of risk factors for the development of PTTNp following various oral and maxillofacial surgery procedures have been identified in the literature. Marchiori et al. found that gender, older age, and depression were risk factors for developing neuropathic pain after orthognathic surgery . In a stPatients that experience PTTNp often report moderate to severe pain levels and the symptoms typically persist. In a study by Van der Cruyssen et al. of patients with PTTN, 86.2% of patients still complained of symptoms after 2 years. The greatest improvement in symptoms occurred during the first 20 weeks after injury with little improvement seen after 60 weeks and lingual nerve injuries had the best long-term outcomes when compared to IAN injuries , 15.n = 10), incomplete recurrence (n = 11), and no recurrence (n = 7). Among the 3 groups there was no statistical difference in preoperative pain intensity (p = 0.16). However, there were statistical differences at 3 months postoperative (p = 0.007), 6 months (p < 0.001), and 12 months (p < 0.001). The average preoperative pain scores of patients with no recurrence of PTTNp post-surgery was 5.57, incomplete recurrence was 7.5, and complete recurrence was 6.5. Following microsurgery if there was recurrence of PTTNp it occurred in the first 6 postoperative months. A limitation of this study was that it was underpowered [Patients that present for microsurgical treatment of PTTNp report variable pain levels typically in the moderate to severe range. As a predictor of surgical outcome, it has been shown that preoperative neuropathic pain predicts postoperative neuropathic pain with a positive predictive value of 67% . The assrpowered .p = 0.0412). As well, in the group with pain at 6 months there were more IAN injuries, and a longer duration from nerve injury to microsurgical repair.Recently, the current authors investigated the effect of preoperative pain scores on surgical outcomes in patients with PTTNp. The major improvement of this study was the increase in power. The population was composed of patients that underwent elective trigeminal nerve repairs of the IAN or LN from 2006 to 2021. Patients included in the study had: 1. Neurosensory complaints in the IAN or LN distribution following third molar extraction, dental implant placement, endodontic treatment, orthognathic surgery, or mandibular trauma; 2. Clinical neurosensory testing (NST) and/or Magnetic Resonance Neurography (MRN) findings of a Sunderland Class II to V injury; 3. Clinical neurosensory test-based diagnosis of neuropathic pain that resolved with local anesthetic blocks to the injured nerve preoperatively; 4. pain intensity measured with VAS scores were available preoperatively and at 6 months postoperatively; and 5. any age, gender, or race. All patients included received no post-surgical medical, behavioral, neuromodulatory or neurosurgical management. Patients were excluded if they had any of the following: 1. acute infection at the time of surgery; 2. history of radiation therapy to the head and neck; 3. current or previous malignancy of the head and neck; 4. medication-induced osteonecrosis of the jaw; 5. demonstrated persistent PTTNp after peripheral trigeminal nerve blocks or in response to control nerve blocks; 6. did not have postsurgical neurosensory and neuropathic testing. Fifty-three patients with preoperative PTTNp of either the LN or IAN who underwent microsurgical treatment were divided into two groups: PTTNp present at 6 months and PTTNp not present at 6 months. The average pain level as measured by Visual Analog Scale (VAS) in the group with no pain at 6 months was 6.4, while the group with pain at 6 months had an average score of 7.75 . There wn = 17), to a cohort with no pain (n = 48), there was no significant difference in injury to surgery duration between the two groups. The study noted, however, that injury to surgery time was nearly significant and may be a significant variable in a larger cohort of patients [Time is a known factor that influences outcomes of nerve surgery. In cases of severe nerve injury that require repair, functional sensory recovery is higher in patients that undergo microsurgical repair within the first 3 months following injury , 21. Intpatients .The current authors recently investigated the effect of time on surgical outcomes in patients with preoperative PTTNp. The population was composed of patients that underwent elective trigeminal nerve repairs of the IAN or LN from 2006 to 2021. The inclusion and exclusion criteria were the same as previously described in this article. Sixty-three patients with preoperative PTTNp who underwent microsurgical repair were divided into four cohorts based on time from injury to surgery: Cohort 1 (0–100 days); Cohort 2 (101–200 days); Cohort 3 (201–300 days); and Cohort 4 (>300 days). The primary outcome was the presence or absence of PTTNp at the 6-month postoperative visit. There was statistical difference in the primary outcome between the cohorts (p = 0.0002). It was found that when the time from injury to surgery was 200 days or less, the percentage of patients with PTTNp before surgery with no neuropathic pain at the 6 month follow up was greater than 60%. When the injury to surgery time was greater than 200 days, just 12% of patients had no PTTNp at 6 months follow up .In the treatment of nerve injuries, time is an important factor. Recent findings from our group show that operative delay has a negative impact on the surgical treatment of PTTNp. As well, patients with recurrence of PTTNp at 6 months often have more intense pain prior to surgery. It was also found that in patients with more intense pain prior to surgery, there was a longer injury to surgery duration. This may imply that if PTTNp persists, pain intensity may increase over time. While these findings are promising, there remains the fact that some patients with PTTNp recover spontaneously or by non-surgical treatment following nerve injury . Before The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.Ethical review and approval was not required for this study in accordance with the local legislation and institutional requirements.TN and JZ wrote, critically read, and edited the manuscript. Both authors contributed to the article and approved the submitted version.JZ is a paid consultant for AxoGen Inc., but this submission was not supported by or reviewed by AxoGen Inc. The remaining author declares 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.


Each patient received two treatments of three minutes each and spaced 60 min apart at a distance of 5 mm from the RU. From a sample of 30 ulcers in patients treated for RU with an average age of 37 years, they stated that the pain decreased considerably and without the need for ingestion of analgesics and antibiotics. Regeneration took place in an average of three days. The NTP proved to be an excellent therapeutic alternative for the treatment of RU since it has a rapid effect of reducing pain and inflammation, as well as adequate tissue regeneration.Recurrent aphthous stomatitis (RAS) is a common disease in the oral cavity characterized by recurrent ulcers (RU). Usually, these cause acute pain without definitive treatment. The present study determines the efficacy of non-thermal plasma (NTP) for treating RU. NTP is applied to the patient’s RU using a radiofrequency generator connected to a point reactor. The power density applied to the ulcer is 0.50 W/cm Recurrent aphthous stomatitis (RAS) is a disease that affects approximately 20% of the population, although the impact varies according to ethnic group and socioeconomic status ,2. It isThe etiology of RAS remains unclear, so various factors have been proposed: immunological, hereditary, genetic, allergic, nutritional and microbial, as causative agents and there are no efficient curative treatments. Various treatments for RUs have been reported to heal these types of injuries or reduce pain ,9,10,11.2), superoxide (O2−), ozone (O3), hydroxyl radical (OH) and hydrogen peroxide (H2O2); and the reactive nitrogen species (RNS), such as nitric oxide (NO), nitrogen dioxide (NO2), nitrogen trioxide (NO3), nitrous oxide (N2O), nitrogen oxide (N2O4) and positive ions such as N2+, of considerable importance in biomedicine [From the physical point of view, plasma is defined as the fourth state of matter. Depending on the thermal balance between electrons and atoms or gas molecules, it can be classified as a thermal plasma or non-thermal plasma . Non-themedicine ,30,31,32Nowadays, application of NTP is used in biomedical procedures , such asFourteen patients were selected who attended the Orocentro Clinic of the Dentistry Faculty from the Mexico State Autonomous University due to ulcers diagnosed as RU. The patients were over 18 years old, of both genders, without systemic compromise and agreed to participate in the study by signing an informed consent. Patients with oral soft tissue diseases, maxillary orthopedic, orthodontic treatment and those with maladjusted dental prostheses were excluded.A longitudinal study was carried out to evaluate the tissue repair time of recurrent ulcers and the presence of pain. Once it was completed and the patient medical history had established the diagnosis of RU, data of size and location of ulcer were recorded, as well as the evaluation time and pain intensity. Pain intensity was measured using the 10-point visual analog scale  . Once thLC resonant load, avoiding use of a matching network, where L is a non–linear inductor and C is the resultant capacitance of a coaxial cable connected to an ergonomic plasma reactor. The RF power generator is based on the 13.56 MHz class E RF module, which is supplied by three dc voltage sources, one of them providing an adjustable voltage magnitude represented by DCV. The available electric power at the RF module output terminals RFP is controlled by the magnitude of the applied dc voltage (DCV) [The proposed atmospheric pressure NTP system is constituted by a radiofrequency (RF) power generator directly coupled to an ge (VDC) .2, less than 4 W/cm2. With this irradiance, it is guaranteed that there is no biological risk, according to the data of the International Commission on Non-Ionizing Radiation Protection [For the NTP application generated with helium gas, the operating parameters reported in previous works were considered ,36. Thesotection . In the For the statistical analysis, descriptive and comparative studies were performed on ulcer type (Fisher’s exact test). Comparative analyzes  for pain and lesion size were also achieved.We measured the size of the ulcer and the erythematous contour in each case and took a photographic record. The sample consisted of 14 patients, of whom nine were women (64.3%) and five were men (35.7%). The age range was from 18 to 67 years old, with a mean of 37 years old. The patients presented from one to five ulcers, resulting in 30 ulcers. Of these, 19 (64%) were minor RU, 10 (33%) corresponded to major RU and 1 (3%) was herpetiform RU. The distribution of oral RU cases is shown in p < 0.05—Fisher’s exact)  see .p = 0.000). After performing the previous review in all cases after the second NTP application, six cases (20%) showed tissue regeneration in the ulcer, considering them repaired at zero days. In this exact measurement, 18 (60%) of the cases reported asymptomatic and the other 12 (40%) cases reported decreased pain with a mean of 4. At 24 h after the two applications with NTP, 11 cases (37%) showed total repair and the remaining 19 cases (63%) showed a reduction in the ulcer size of between 1 and 6 mm with a mean of 3 mm. Regarding the sensation of pain, when assessing the 30 cases, 27 (90%) reported asymptomatic, two cases (7%) reported pain with a value of 1 and the other case (3%) presented pain decreasing from a value from 7 to 4 on the visual analog scale. Ulcer repair time ranged from one hour to 7 days, with a mean of 3 days. In a single case, the ulcer persisted after applying NTP; in addition to the patient reporting pain, the patient reported positive for smoking. The time it took for the ulcers to regenerate showed a correlation only with the ulcer’s initial size of 0.703 . RAS healing is a highly specialized process for repairing damaged/injured tissues through various therapies. Failures in the normal healing process of these ulcers lead to abnormal scar formation and a chronic state that is more susceptible to infection. Wounds caused by RU affect patients’ quality of life, which is why there is an urgent demand for the development of competitive therapies. There are new developments in advanced technologies for the care of RU, for example, laser technology ,41,42, np = 0.0001). Additionally, at 24 h, 90% of the cases reported being asymptomatic, 7% reported pain with a value of 1 and 3% (one case) reported pain with a value of 4. In this regard, it is essential to point out that the two cases that reported pain with a 1 value correspond to a patient with a significant RAS whose ulcers measured 15 and 19 mm. The case that reported pain with a value of 4 is a smoker and the only case that took seven days to heal; therefore, it is crucial to advise smoking patients with RAS to stop smoking during treatment.NTP at atmospheric pressure was applied to the ulcer in the cheek, labial mucosa, tongue, oropharynx, mouth floor, soft palate and gingiva. In, patients with RAS and treated with NTP, its anti-inflammatory and healing effect is evident since ulcer size and pain are significantly reduced. A notable improvement was observed since 86% of the patients did not report pain after one hour of application, being statistically significant  and nitric oxide (NO), is essential in wound healing beyond the simple oxidative elimination of pathogens. The importance of these elements lies in infection prevention, the induction of angiogenesis, the keratinocyte’s increase in differentiation and migration, and the increase in the proliferation of fibroblasts and collagen synthesis. Furthermore, NO has been demonstrated to participate in an intercellular communication network during the healing process, regulating the behavior of macrophages, keratinocytes and fibroblasts [The findings of this study demonstrated the absence of adverse reactions in the tissues. That is, managing recurrent ulcers with NTP was safe for all treated patients since no case showed adverse effects at six months of follow-up and there was significantly reduced pain levels and repair time after the application of NTP. This could be explained due to the mechanism of action of NTP. Most authors agree that treatment with NTP accelerates wound healing by decreasing the level of inflammatory factors and bacterial load and has anti-neoplastic effects . Reactivroblasts . That isThe study showed that the application of non-thermal plasma in recurrent aphthous stomatitis reduces the levels of pain sensation in the patient, accelerates the healing of the RU and does not produce adverse effects. The technology allowed a quick recovery of the patient and, consequently, a reactivation of daily life. The NTP application in the RUs enables its repair. NTP is an excellent therapeutic alternative for RUs that afflict patients since it provides rapid control of pain and inflammation, accelerating the natural healing process. Due to its application characteristic, it does not bother patients.


Purpose: Two-stage tissue expander (TE) to implant breast reconstruction is commonly performed by plastic surgeons. Prepectoral implant placement with acellular dermal matrix  reinforcement is evidenced by minimal postoperative pain. However, the same is not known for TE-based reconstruction. We performed this study to explore the use of complete AlloDerm® reinforcement of breast pocket tissues in women undergoing unilateral or bilateral mastectomies followed by immediate, two-stage tissue expansion in the prepectoral plane.Methods: Patients (n = 20) aged 18-75 years were followed prospectively from their preoperative consult to 60 days post-TE insertion. The pain visual analog scale (VAS), Patient Pain Assessment Questionnaire, Subjective Pain Survey, Brief Pain Inventory-Short Form (BPI-SF), postoperative nausea and vomiting (PONV) survey, BREAST-Q Reconstruction Module, and short-form 36 (SF-36) questionnaires were administered. Demographic, intraoperative, and 30- and 60-day complications data were abstracted from medical records. After TE-to-implant exchange, patients were followed until 60 days postoperatively to assess for complications.Results: Pain VAS and BPI-SF pain interference scores returned to preoperative values by 30 days post-TE insertion. Static and moving pain scores from the Patient Pain Assessment Questionnaire returned to preoperative baseline values by day 60. The mean subjective pain score was 3.0 (0.5 standard deviation) with seven patients scoring outside the standard deviation; none of these seven patients had a history of anxiety or depression. Median PONV scores remained at 0 from postoperative day 0 to day 7. Patient-reported opioid use dropped from 89.5% to 10.5% by postoperative day 30. BREAST-Q: Sexual well-being scores significantly increased from preoperative baseline to day 60 post-TE insertion. Changes in SF-36 physical functioning, physician limitations, emotional well-being, social functioning, and pain scores were significantly different from preoperative baseline to day 60 post-TE insertion. Five participants had complications within 60 days post-TE insertion. One participant experienced a complication within 60 days after TE-to-implant exchange.Conclusions: We describe pain scores, opioid usage, patient-reported outcomes data, and complication profiles of 20 consecutive patients undergoing mastectomy followed by immediate, two-stage tissue expansion in the prepectoral plane. We hope this study serves as a baseline for future research. Breast reconstruction is typically performed using implants or autologous tissue transplantation. Though autologous transfer is considered the gold standard for restoration to match the original breast, particularly in irradiated patients, implant-based breast reconstruction remains the most widely used approach in the United States, and the case numbers continue to rise ,2. ImplaTraditionally, two-stage breast reconstruction involved total submuscular coverage of the TE/implant beneath the pectoralis major and serratus anterior . Though Prepectoral TE breast reconstruction with ADM presents an opportunity to improve upon the current reconstructive methods and minimize postoperative pain. However, little is known regarding the effectiveness of ADM in pain reduction using a two-stage reconstructive approach in the prepectoral plane ,8. We pePatient recruitmentClinicalTrials.gov<http://ClinicalTrials.gov> Identifier: NCT03195322) was approved by the Johns Hopkins Medicine Institutional Review Board (IRB00091477). Patients aged 18-75 years undergoing unilateral or bilateral mastectomies followed by immediate, TE placement in the prepectoral plane with complete AlloDerm® coverage were eligible for inclusion. Patients were excluded if they (1) underwent final reconstruction with autologous material, (2) were allergic to cefoxitin, lincomycin, vancomycin, or polymyxin, (3) had active connective tissue disease, or (4) were current smokers.This clinical trial  , the PatOn postoperative day 0, immediately following TE placement, the pain VAS, Patient Pain Assessment Questionnaire, BPI-SF, and postoperative nausea and vomiting (PONV) intensity scale were administered . These sLong-term quality-of-life and health outcomes assessments were performed on postoperative days 30 ± 4 and 60 ± 7 post-TE placement. During these visits, pain scores , postoperative BREAST-Q reconstructive module surveys , and SF-Statistical analysisStatistical analyses were performed using IBM Statistical Package for the Social Sciences (SPSS) software version 27 . Data on pain VAS scores, static and moving pain scores from the Patient Pain Assessment Questionnaire, BPI-SF pain interference scores, opioid use, BREAST-Q scores, and SF-36 subscores were analyzed descriptively with median and interquartile range. Comparisons across timepoints for BREAST-Q and SF-36 scores were conducted by non-parametric Kruskal-Wallis test. Significance was assessed at a two-sided p-values < 0.05.Patient demographic and intraoperative dataA total of 39 breasts in 20 consecutive female patients were reconstructed between October 2017 and December 2018. The mean age was 42 years (range: 29-56), and BMI was 25.1 (range: 12.8-35). The majority of patients were white (80%), married (75%), and did not have a history of smoking (85%). Anxiety (10%) and depression (15%) were reported in our patient cohort. Tumor data are contained in Table The most common tumors were ER/PR+ (43.8%) with three being triple-negative 25%). Indications for surgery were invasive cancer (n = 14), ductal carcinoma in situ (n = 2), atypical lobular hyperplasia (n = 1), and prophylactic due to BRCA mutation (n = 3). Of our patient cohort, six patients received neoadjuvant chemotherapy and one received radiation after TE placement. Intraoperative data were collected in Table 5%. IndicMost patients received a 400 cc TE (37.5%) that was filled with air (60%). Mastectomy followed by immediate prepectoral TE placement with AlloDerm® was performed on bilateral breasts (n = 18) and unilaterally on the right breast (n = 1). For the second stage of reconstruction, 13 patients underwent TE exchange for a permanent implant  and the least pain in the last 24 hours was 2.0  Table .Patient-reported static pain scores were highest on post-op day 1 for “Sitting up in bed” . Moving pain scores showed the highest score on postoperative day 1 for “Carrying groceries” . All static and moving pain scores progressively declined to preoperative values by day 60. The mean subjective pain score was 3.0 (0.5 standard deviation). None of the seven patients scoring outside the standard had a history of anxiety or depression. BPI-SF pain interference scores followed a similar trend to pain VAS Figure .PONV scores and opioid useMedian PONV scores remained at 0 from postoperative day 0 to day 7 Table .Opioid use decreased across all participants over the postoperative period. From our patient cohort, opioid use was reported on post-TE placement day 1 (n = 17) and decreased on day 7 (n = 10). By day 30, opioid use was still reported (n = 2). One patient reported pain bilaterally at the axillae, lower ribs, and left medial arm and forearm; the other reported pain at the sternoclavicular joint and right axilla. By day 60, only one patient reported opioid use without specifying her pain location Table .Most participants (n = 19) reported non-opioid analgesic use, most notably gabapentin and acetaminophen (Tylenol), through day 30.Quality of life: BREAST-Q and SF-36Changes in BREAST-Q scores for satisfaction with breasts, psychosocial well-being, and physical well-being: Chest was not significantly different across time points. BREAST-Q sexual well-being scores significantly increased from preoperative to postoperative day 60 time points Figure , Table 6SF-36 emotional limitations and energy/fatigue scores did not differ significantly across time points Figure , Table 6SF-36 physical functioning scores significantly decreased from preoperative to postoperative day 7 time points and increased from postoperative day 7 to postoperative day 30. SF-36 physical limitations scores decreased nonsignificantly from preoperative to postoperative day 7 time points, did not change from postoperative day 7 to day 30, and increased from postoperative day 30 to day 60; SF-36 emotional well-being scores followed similarly. SF-36 social functioning scores significantly decreased from preoperative to postoperative day 7 time points and increased from postoperative day 7 to day 60; SF-36 pain scores followed similarly.30- and 60-day complicationsSerratia marcesens (Table One participant (5.6%) experienced an adverse event within 30 days postoperatively. This participant was admitted for an infected left breast seroma. Treatment included IV antibiotics and ultrasound-guided drainage. Two participants (11.1%) experienced a serious adverse event within 30 days postoperatively. The first participant developed left breast cellulitis with wound cultures growing ns Table .She was admitted to the hospital for five days, underwent TE removal, and received IV antibiotics. The second participant underwent TE exchange due to recurrent breast seromas. Two participants (11.1%) experienced serious adverse events within 60 days postoperatively. The first participant experienced bilateral wound dehiscence and required bilateral TE removal. The second participant experienced a right breast seroma that required drainage in the clinic and eventual right TE removal. Five patients experienced complications within 60 days post-TE placement, and the complication rate was calculated to be 25%. Three patients underwent TE removal within 60 days postoperatively, and a removal rate was calculated to be 15%. After TE-to-implant exchange, only one patient experienced a complication within 60 days postoperatively.In this prospective study assessing postoperative pain in patients who underwent unilateral or bilateral mastectomies followed by immediate TE placement in the prepectoral plane with complete AlloDerm® reinforcement, we found that patient-reported pain scores returned to baseline by postoperative day 30. Pain is a crucial factor to control during the recovery period. It is known that many surgeons utilize ADM for lower pole reinforcement in implant- or TE-based reconstruction since they believe ADM reduces postoperative pain, though the evidence is conflicting . HoweverFor a direct comparison of pain VAS scores, McCarthy et al. described a mean pain VAS score of 5.5 ± 2.8 (standard deviation) recorded on day 1 after TE insertion in the subpectoral plane with AlloDerm® . Our meaPatient-reported pain was successfully recorded by our surveys, but previous studies had not reported on static and moving pain. These measures could potentially give an insight into the patient's experience of pain after discharge. Physicians can utilize these scores to advise patients to be aware of certain activities that would elicit the most pain during the recovery period.Additionally, we report a wide variety of baseline perceptions of pain from our Subjective Pain Survey. Though anxiety and depression have been associated with increased perception of acute pain, this was not the case in our cohort . HoweverOur study also reports BPI-SF pain interference scores and PONV scores within 60 days after TE placement, which are not commonly described in the literature. One study by Park et al. recorded BPI-SF pain interference and PONV scores after ultrasound-guided blocks of the erector spinae muscles before mastectomy with TE reconstruction in the subpectoral plane . They onWhen comparing opioid usage between prepectoral versus subpectoral reconstruction, one study has shown a reduction in immediate postoperative utilization of opioids in their prepectoral versus subpectoral cohorts . Van BoeReduction of opioid usage is important in the recovery period, but overall success can be best defined through patient satisfaction. Previous studies have shown that BREAST-Q scores do not differ significantly across domains in patients receiving immediate, TE-based prepectoral versus subpectoral breast reconstruction . The sigRegarding function, SF-36 data showed significant differences between the scores of physical functioning, physical limitations, and pain from preoperative baseline to day 60 post-TE insertion. Though previous studies have shown that postoperative SF-36 summary physical health scores were lower among patients who received prepectoral versus subpectoral TE placement, our study demonstrates the potential for patients to return to their preoperative baseline score by day 60 . Future Patient-reported outcome scores are effective in determining patient satisfaction and quality of life, but it is also important to address postoperative complications. There is no consensus on whether prepectoral versus subpectoral placement is associated with more complications, but prepectoral has been associated with higher seroma rates ,28. ThouThis study has several limitations. Although this study had a relatively consistent and thorough follow-up, some questionnaires were incompletely answered resulting in a loss of data. This study originally intended to utilize 3D imaging techniques to capture changes in the postoperative period in prepectoral reconstruction; however, variations in imaging prohibited abstraction of data and inclusion in our final analysis. As a result, postoperative scars were not able to be assessed. We also did not analyze preoperative analgesia by our anesthesia team, which may have confounded pain scores. Finally, this study is descriptive in nature and reports the postoperative time course in pain and opioid use. These findings do not substantially add to the literature, but the prospective, quality of life data presented are valuable data that may aid in future studies.This prospective study described postoperative measures of pain VAS scores, Patient Pain Assessment Questionnaires, Subjective Pain Surveys, BPI-SF pain interference scores with pain medication usage, PONV scores, and BREAST-Q and SF-36 survey scores in patients who underwent mastectomies followed by two-stage reconstruction with tissue expansion and implant placement in the prepectoral plane. Our findings show that pain scores return to baseline by postoperative day 30 with 90% stopping opioid use by that time as well. BREAST-Q sexual well-being scores at postoperative day 60 were higher than preoperative scores, which have not been previously reported in the literature. Future studies are required to understand the utility of ADM in TE-based breast reconstruction in the prepectoral plane.