Erector spinae plane block (ESPB) is a novel inter-fascial plane block, which is applied more and more in postoperative pain control, especially in chest surgery. Regional block is advocated in order to decrease opioid consumption and improve analgesia in urological surgery. Therefore, we aimed to explore whether ESPB would have similar analgesia compared with thoracic paravertebral block (TPVB) in laparoscopic nephroureterectomy.This prospective, randomized, double-blinded, non-inferiority trial will enroll 166 patients undergoing laparoscopic nephroureterectomy. Participants will be randomly assigned 1:1 into receiving ESPB or TPVB before surgery. Both ultrasound-guided ESPB and TPVB will be performed with an injection of 0.375% ropivacaine 0.4 ml/kg before anesthesia induction. Standardized patients controlled intravenous analgesia (PCIA) will be applied for each patient. The primary endpoint is the joint of cumulative 24 h opioid (sufentanil) consumption and average pain score via numeric rating scale (NRS) at 24 h after surgery. Secondary endpoints include rescued analgesic demand, cumulative opioid consumption, and pain NRS scores at different preset timepoints within 48 h after surgery. Other predefined outcomes include clinical features of blockage, quality of recovery, subjective sleep quality, time to ambulation and diet, and adverse events, as well as length of stay in hospital and anesthesia cost.Previous studies investigating the analgesic efficacy of ESPB only concentrated on a single endpoint for postoperative pain evaluation, while studies focusing on the direct comparison between ESPB and TPVB in urological surgery are still lacking. Our study is the first trial in non-inferiority design of comparing ESPB and TPVB in patient undergoing laparoscopic nephroureterectomy, and the primary outcome is the joint endpoint of opioid consumption and pain NRS score.ChiCTR 2000031916. Registered on 14 April 2020.Chinese Clinical Trial Registry The online version contains supplementary material available at 10.1186/s13063-021-05173-0. Our study is the first trial in non-inferiority, double-blinded design of comparing ESPB with TPVB for analgesia in laparoscopic nephroureterectomy.The primary outcome in our study is set as a joint endpoint of opioid consumption and pain NRS scores, both of which are deemed equal important in evaluating pain control.This study will investigate not only erector spinae plane block efficacy of analgesia, quality of postoperative recovery as usual, but also its clinical features of blockage.The relatively small sample size may limit to discriminate the safety consideration between the two blocks technique.A single-center trial design may limit its universality.Upper tract urothelial carcinoma (UTUC) includes carcinoma of the renal pelvis and ureter, as well as bladder. According to the study of European and American population, UTUC accounts for 5–10% of all urothelial carcinoma [A previous study has shown that patients often suffered moderate to severe pain after laparoscopic nephroureterectomy . AdequatThoracic paravertebral block (TPVB) is a classic trunk block with definite analgesic effect for both somatic and visceral pain. Its efficacy has been demonstrated in urological surgery –5.Erector spinae plane block (ESPB) is a novel inter-fascial plane block first introduced by Forero et al. in 2016 –9, laparCompared with TPVB, ESPB has the following advantages. First, the dermatomal distribution of sensory loss is extensive, which covers the area ranging from the ipsilateral parasternal to the midline of the lower back in a single shot block. It has been reported that ESPB performed at T5 level can give a sensory loss dermatome from T2 to T9 , 17, whiAlthough studies have shown that ESPB has a better analgesic effect comparing with traditional opioid intravenous analgesia, there is still a lack of evidence in direct comparing the analgesic efficacy between ESPB and TPVB in urological surgery. Besides, most of previous studies just chose a single endpoint for postoperative pain evaluation and the follow-up period is often limited within 24 h after surgery. Our study is the first trial in non-inferiority design in comparing of ESPB and TPVB with a 48 h follow-up after surgery in patient undergoing laparoscopic nephroureterectomy, and the primary outcome is a joint endpoint of opioid consumption and pain NRS  scores.The aim of this study is designed to compare ESPB with TPVB in terms of the efficacy of analgesia, the quality of postoperative recovery, and clinical features of blockage in laparoscopic nephroureterectomy. We hypothesize that the analgesic efficacy of ESPB is non-inferior to that of TPVB for patients undergoing laparoscopic nephroureterectomy.This trial is a prospective, single-center, two-arm, double-blinded, non-inferiority randomized controlled trial. The study is initiated by Peking University First Hospital, and its design has been completed in strict accordance with the SPIRIT 2013 statement  on 29 March 2020 with the latest version 1.1. This trial has been registered on Chinese Clinical Trials registry (identifier: ChiCTR2000031916). We will strictly adhere to the Good Clinical Practice guidelines and the Declaration of Helsinki during the whole period of the study. The flowchart diagram of the study is illustrated in Fig. On the day before surgery, patients will be screened by an investigator according to the inclusion/exclusion criteria. If the operation is on Monday, the screening will be performed on the previous Friday. Written informed consent will be obtained from each participant before the enrolment. Patients will be instructed how to self-assess pain severity via the numeric rating scale .Between 18 and 75 years of age;Plan to undergo laparoscopic nephroureterectomy;Agree to receive regional nerve block and postoperative intravenous controlled analgesia (PCIA);American Society of Anesthesiologist (ASA) physical status classification I–III.Participants who meet all of the following criteria will be enrolled in this study:Refuse to participate in this study;2 or < 15 kg/m2;BMI > 35 kg/mCombined with severe comorbidities, including but not limiting to renal dysfunction , liver dysfunction (Child-Pugh class C) and heart failure, or ASA physical status classification ≥ IV;Contraindication of deep nerve block, including but not limiting to be allergic to anesthetic drug, coagulation disorder, and infection at the injection site;Chronic opioids dependence or chronic pain over 3 months;Unable to communicate preoperatively due to severe dementia, language barrier, or neuropsychiatric disorder;Unable to perform nerve block procedure due to difficult anatomy through ultrasound scan.Participants will be excluded if they have any of the following conditions:The SAS 9.3 software package  is used to generate random numbers with a block size of 4 by biostatisticians who will not participant in the statistical analysis of the data. The random sequence will be sealed in consecutively numbered opaque envelopes and kept by the study coordinator. Participants will be randomly divided into two groups according to the 1:1 ratio of ESPB group and TPVB group. A research coordinator is designated to distribute and preserve randomization result. The coordinator will open the envelopes for allocation according to the order of enrolment and prepare the study drug.The participants will be blinded to the allocation. Because the needle injection of ESPB and TPVB are very close, participants themselves could hardly detect the clinical differences. Anesthesiologists who perform the nerve block and take charge of intraoperative management and surgeons are independent individuals. Only the random sequence number rather than the specific nerve block type will be recorded in the electronic anesthesia information management system (AIMS). Researchers who do not take part in the nerve block and intraoperative management are designated to postoperative follow-up. Besides, trained anesthesiologist who do not perform the block will be designated to evaluate the clinical features of the block objectively. When case report forms (CRFs) are written and checked, the data will be monitored periodically by the Clinical Research Ethics Committee of Peking University First Hospital. After the database is locked, allocation will be handed over and revealed to statistical analysis.Participants will be admitted to the preoperative preparation area 30 min earlier before transferring to operating room (OR). After establishment of standard monitoring and intravenous access, premedication with 0.02 mg/kg midazolam or 0.08 μg/kg sufentanil will be administrated if necessary. Before regional block, all patients will be positioned lateral decubitus with the operative side up and received ultrasound scan by two experienced anesthesiologists who will not take part in perioperative management and follow-up. After being confirmed as suitable participants for nerve block, patients will receive ultrasound guided ESPB or TPVB block according to the randomized grouping allocation. The drug used for both interventions is the same with a bolus of 0.375% ropivacaine in the volume of 0.4 ml/kg. Once the block is completed, the dermatomes of sensory loss will be assessed by ice-tactus tests every 5 min. Both the onset time (defined as the time to the first detection of a blocked dermatome) and time to fixed sensory block (defined as the time when there was no further extension of the blocked dermatomes) will be recorded. Decreased or loss off thermic sensation of any region will be regarded as successful sensory loss  will be traced by sliding the probe medially and then marked. The probe will be then traced cranially to locate the T10-T11 vertebral. After the same marked method, the probe will be continually moved 3–5 cm laterally and rotated in transverse orientation to identify the muscle layers of erector spinae and transverse processes near the marked site.After re-confirming the important anatomic structure including lumbar artery under ultrasound scan, a 22-gauge nerve block needle  will be inserted in-plane through a medial-lateral direction. Once the needle tip arrives beneath the erector spinae muscle, 3 ml of normal saline will be injected firstly to ensure correct positioning of the needle after aspiration. The prepared study drug will be then injected into this plane with aspiration every 5 ml per injection in case of accidental puncture of vessel or pleura. Successful study drug injection is defined as the appearance of a hypoechoic ellipsoid with well-defined margin beneath erector spinae muscle on ultrasonic view.T10 and T11 vertebral will be located and marked as the same way as that mentioned above in ESPB group. The probe will then be moved 3–5 cm laterally to identify the paravertebral space as the target injection site. After probe being rotated into transverse orientation, a 22-gauge nerve block needle  will be inserted using the in-plane technique. Once the needle threads the internal intercostal membrane and arrives in the paravertebral space, 3 ml of normal saline will be injected firstly. If displacement sign of the pleura occurs, the prepared study drug will be then injected into the confirmed paravertebral space. Successful study drug injection is defined as the appearance of pleura displacement sign and hypoechoic ellipsoid in paravertebral space under ultrasonic view.2O/sevoflurane inhalation to maintain sedation level within the range of 40–60 under bispectral index (BIS) monitor. Opioid analgesics (remifentanil TCI together with sufentanil intermittent administration on demand) are used to maintain analgesia. During the surgery, the fluid volume and infusion speed are adjusted according to hemodynamic monitoring conditions to maintain the blood pressure within 20% of the baseline values. All surgical procedures are performed by fixed surgical team members, and the pneumoperitoneum pressure is often maintained at 12–16 mmHg as usual. After the surgery, standardized patient controlled intravenous analgesia pump is applied for each patient, which was established with 1.25 μg/ml sufentanil and programmed to deliver 4-ml boluses with a lock-out interval of 10 min and no background infusion rate. Patients who are enrolled for this trial will be trained to use a patient controlled intravenous analgesia pump before surgery.Intraoperative anesthesia management is performed by an attending anesthesiologist and an assistant; none of whom has knowledge of the allocation. Prednisone methylprednisolone (40 mg) is administered before anesthesia induction, followed by intravenous anesthesia induction with sufentanil (0.1–0.3 μg/kg), propofol (1–2 mg/kg), and rocuronium (0.6 mg/kg). Anesthesia is maintained by intravenous anesthesia combined with or without NThe primary outcome in this trial is a joint endpoint of cumulative 24 h opioid consumption after surgery and average pain NRS score at 24 h  postoperatively.Cumulative opioid consumption at other different times  after surgery, as well as the time interval to the first bolus demand in PCIA pump, the numbers of required and administered boluses in PCIA pump.Somatic and visceral pain NRS scores both at rest and with movement at preset timepoints  postoperatively.Besides PCIA pump, demand of other rescue analgesic .Clinical features of blockage including time-consumption for the intervention, the onset time and time to fixed sensory block, dermatomal distribution of sensory loss, predefined regional distribution of sensory loss, times of puncture, and the adverse events.Quality of recovery scores (QoR-15) (assessed by QoR-15 questionnaire ) face-toSleep quality scores on the nights of the first 2 days after surgery .The incidence of postoperative vomiting and nausea score assessed with NRS scores (0 = no nausea whereas 10 = severe nausea) at the following timepoints  postoperatively.The incidence of postoperative moderate to severe pain.Overall incidence of postoperative complication  .Time to first ambulation and diet (observation from the end of surgery).Length of postoperative hospital stay and total length of hospital stay.Anesthesia cost and total hospitalization cost.The other endpoints are defined as follows:We will strictly adhere to the steps to minimize the risk of adverse events which might be caused by regional nerve block. First, we will scan eligible patients before the enrolment and exclude those who are difficult for TPVB and ESPB from anatomical point of view. Both blocks will be performed under directly ultrasound guiding by experienced anesthesiologists. Second, the local anesthetic we used for regional block is 1.5 mg/kg ropivacaine (0.4 ml/kg with 0.375% in our study), which has already been proved to be safe in previous studies , 25. ThiBaseline data will be collected, including age, gender, birth date, education years, weight, and height. Co-morbidities as well as important laboratory tests and instrumental examination will be documented. Preoperative recent sleep quality will be assessed with Pittsburgh Sleep Quality Index (PSQI) . IntraopBased on the original observation records of the participants, the data are collected into the case report forms timely, completely, and correctly. All data will be kept confidentially. Data entry will be performed in a double-input and double-check way with the REDCap (Research Electronic Data Capture) database system developed by the Vanderbilt University. The data will be monitored and sampled regularly in the trial by the Clinical Research Ethics Committee, and the database will be locked after the electronic data is checked. After data entry and verification as required are completed, the case report forms will be filed in numbered order and kept in a specific filing cabinet. We have no plan in interim analysis until the target sample size is achieved.The primary endpoint of this non-inferiority trial is the joint of cumulative 24 h opioid consumption after surgery and average pain NRS score at 24 h postoperatively.α = 0.05 and a power of 1-β = 90%, the sample size required to detect difference was 77 patients in each group.In a pilot investigation of our patients, the mean (± standard deviation) of the cumulative 24 h opioid (sufentanil) consumption after laparoscopic nephroureterectomy was about 25.7 (± 2.0) μg with TPVB and 35 (± 14.0) μg with non-block respectively (data were unpublished yet). The non-inferiority margin was set as 5  . With a A 1–1.3 point difference in pain NRS scores is usually considered as acceptable subjective pain discrimination . When thHence, the greater sample calculated above was 77 participants per group. Considering a dropout rate of 5% and technique failure rate of 3%, we finally planned to enroll 83 participants per group . The sample size was estimated by the PASS software .t test or Mann-Whitney U test according to data distribution. Categorical data will be expressed as numbers (percentages) and tested by chi-square test/Fisher’s exact test. Time-to-event data will be analyzed by the Kaplan-Meier estimator, with the difference between groups tested by the log-rank method. Two-tailed p values of less than 0.05 are regarded as statistically significant. All statistical analyses are performed with the SPSS 25.0 statistical package .Baseline characteristic will be compared according the data distribution and type. In addition to graph method for qualitative analysis, Shapiro-Wilk test will be also used for quantitative analysis in review of data distribution. Continuous data with normal or approximate normal distribution will be expressed as mean ± standard deviation, while continuous data with non-normal distribution is expressed as median . Continuous data will be tested by independent sample Cumulative 24 h opioid consumption and average pain NRS score at 24 h after surgery is the primary joint endpoint, which will be analyzed by “joint hypothesis test.” In this analysis, the intervention group could be considered effective as long as either of the two endpoints is non-inferior. The confidence interval method will be used to perform the non-inferiority test, and the result will be expressed as effect size (difference) (95% CI). If the effect size upper limit of the one-side 95% CI is smaller than 5 in cumulative 24 h opioid consumption, we will conclude that ESPB is non-inferiority to TPVB; in addition, when average pain NRS scores at 24 h after surgery is smaller than 1, ESPB group will be also considered non-inferiority.α of 0.025 with Holm-Bonferroni correction for testing both outcomes . If superiority is detected on at least either cumulative 24 h opioid consumption or pain NRS scores, the ESPB group will be claimed to be better than TPVB group.If non-inferiority is conducted for the primary outcome, the superiority of the corresponding comparison will be evaluated for each outcome using an overall t test will be used for comparison if the distribution accords normality assumption; if distribution is skewed as well as not independent at different timepoints, the difference will be determined by Mann-Whitney U test.For the opioid consumption and pain NRS scores at other different timepoints after surgery, repeated measure ANOVA  will be performed if normality and homogeneity of variance and sphericity hypothesis (Mauchly’s test) are met. If not, one-way ANOVA and its correction (Greenhouse-Geisser coefficient correction and Huynh-Feldt coefficient correction) as well as generalized estimated equation (GEE) model will be performed. As for inter-group comparison, independent sample Outcome analyses will be performed in the intention-to-treat (ITT) population, i.e., all patients are analyzed in the group to which they are randomized and received at least part of study intervention. A per-protocol (PP) analysis will be also performed for the primary endpoint. Statistical analysis will be performed by professional biostatisticians. All conclusions will be based on the original data.Clinical anesthesiologists are always looking for a more convenient, effective, and safer analgesic method to control acute pain after surgery. Regional block has become an important role of perioperative multimodal analgesia nowadays. ESPB is thought to be a promising inter-fascial block due to its reliable opiate-sparing effect and easy performing characteristic . AlthougEpidural block was recognized as the golden standard analgesia in abdominal surgery in the past decades; however, regional block is mounting to an important position in the area of acute pain management for its convenience and safety. Paravertebral block is deemed as a premium alternative to epidural block and has been used for many years in various kinds of surgery due to its definite analgesia . Most ofAs for pain evaluation, most studies have concentrated on the opioid consumption or pain severity separately, but in fact, these two components contribute equal importance to pain evaluation . TherefoUTUC patients undergoing laparoscopic nephroureterectomy are deemed as a good observation population, due to the incisions of this surgery located both in the lateral and lower abdomen wall and the high incidence of moderate-severe pain after surgery. To our knowledge, this study is the first one to compare ESPB with TPVB in regard to the efficacy and safety in patients undergoing laparoscopic nephroureterectomy. The result might have an influence on enhanced recovery (ERAS) management in urological surgery.This study is currently at the patient enrolment and data collection stage. The current version of the study protocol is version 1.1 and was approved on 29 March 2020. Patient recruitment started on 27 April 2020 and expected to be finished by 30 May 2022.Additional file 1. SPIRIT 2013 checklist.Additional file 2. Predefined regional distribution.


To assess whether higher dispositional optimism could predict better health-related quality of life (HRQL) after esophageal cancer surgery.This Swedish nationwide longitudinal study included 192 patients who underwent esophagectomy for cancer. The exposure was dispositional optimism measured by the Life Orientation Test-Revised (LOT-R) at 1 year post-surgery. Patients were categorized into four subgroups  based on the quartile of the LOT-R sum score. The outcome was HRQL assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and Quality of Life Questionnaire-Esophago-Gastric module 25 (QLQ-OG25) at 1, 1.5, and 2 years post-surgery. Linear mixed-effects models, adjusted for potential confounders, were used to examine the mean score difference (MSD) with 95% confidence interval of HRQL among the four patient subgroups.Patients with very high dispositional optimism reported clinically relevantly better global quality of life, emotional function, and social function (MSD range 10–16) and less severe symptoms in pain, dyspnea, diarrhea, eating difficulty, anxiety, dry mouth, trouble with taste, worry about weight loss, and self-doubt about body image (MSD range − 9 to − 22) than patients with lower dispositional optimism. Patients with moderately high dispositional optimism reported clinically and statistically significantly better global quality of life (MSD 10) and less severe diarrhea (MSD − 9) than patients with lower dispositional optimism. Adjusted MSDs were constant over the three time points in all aspects except for eating difficulty.Measuring dispositional optimism could help identify patients at higher risk of poor HRQL recovery after esophageal cancer surgery.The online version contains supplementary material available at 10.1245/s10434-021-10026-w. Esophageal cancer is a malignant tumor that ranks as the sixth leading cause of cancer death globally.Dispositional optimism is a relatively stable personality trait, which refers to the global expectation that more desirable than bad things will happen in the future.In this study, we aimed to use Swedish nationwide population-based longitudinal data to assess whether higher dispositional optimism predicts better HRQL after esophageal cancer surgery.Data for this longitudinal study were drawn from a prospective, ongoing Swedish nationwide cohort study entitled Oesophageal Surgery on Cancer patients-Adaptation and Recovery (OSCAR). Detailed description of the OSCAR study has been presented elsewhere.The present study included patients who underwent esophagectomy for cancer between 1 January 2013 and 28 February 2018, and incorporated three follow-up time points at 1, 1.5, and 2 years post-surgery. Patients who died during the follow-up period, had psychiatric history, or were diagnosed with noncancerous neoplasm (dysplasia) were excluded.Dispositional optimism was measured at 1 year post-surgery using the Swedish version of Life Orientation Test-Revised (LOT-R).22Due to the ambiguous dimensionality of LOT-R and absence of psychometric study in patients with esophageal cancer, we conducted a series of confirmatory factor analyses to assess the factor structure of LOT-R. Detailed results can be found elsewhere.The remaining five items of LOT-R were summed, of which the two negatively worded items were reversed. A higher sum score represents higher dispositional optimism. Based on the quartile of the sum score, patients were categorized into four subgroups with very low, moderately low, moderately high, and very high dispositional optimism.HRQL was measured at 1, 1.5, and 2 years post-surgery using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and disease site-specific (Esophago-Gastric) module EORTC QLQ-OG25.25The EORTC QLQ-C30 contains 30 items with Likert scaling and measures HRQL aspects of cancer patients in general. It consists of one global quality-of-life subscale, five functional subscales , three symptom subscales , and six single items .24The EORTC QLQ-OG25 is a 25-item esophagogastric cancer-specific questionnaire, which comprises six symptom subscales  and ten single items .25Missing values in both questionnaires were handled according to the EORTC Scoring Manual,27t-test or analysis of variance (ANOVA). Linear mixed-effects model was used to examine the mean score differences (MSDs) of HRQL among the four patient subgroups with hierarchical dispositional optimism levels. Covariates include time , age (continuous variable), sex , cohabitation status (non-cohabitating or cohabitating), education level , Charlson Comorbidity Index32Sociodemographic and clinical characteristics of all included patients as well as the four patient subgroups were summarized. We compared the overall mean of the LOT-R sum score between patients with different sociodemographic and clinical characteristics using trivial , small , medium , or large .36HRQL measures several aspects; to minimize the type I error due to multiple comparisons, we tested the statistical significance of adjusted MSD only if it had clinical relevance based on evidence-based guidelines.Stata 13 and SAS 9.4 were used for the statistical analyses. All 95% confidence intervals (CIs) were two sided.n = 49), psychiatric history before surgery (n = 5), noncancerous histology (n = 3), and lack of essential data (n = 16), leaving 192 patients included in the analysis. Among them, 170 and 156 patients answered the 1.5- and 2-year questionnaire, respectively.Figure n = 48, LOT-R sum score range 6–13), moderately low , moderately high , and very high . Sociodemographic and clinical characteristics of the four patient subgroups are presented in Table Table In almost all HRQL aspects except for eating difficulty, the predictive effect of dispositional optimism on HRQL was not modified by time. Over the three assessment time points, there was no clinically relevant difference between patients with very low and moderately low dispositional optimism in any HRQL aspect (Supplementary Table S2). However, compared with patients with very low and moderately low dispositional optimism, patients with moderately high dispositional optimism reported clinically relevantly and statistically significantly better global quality of life  and less severe diarrhea . There was no clinically relevant difference between patients with moderately low and very low dispositional optimism, or between patients with moderately high and lower (very low/moderately low) dispositional optimism  and a disease-specific module (EORTC QLQ-OG25). Moreover, the clinical relevance of adjusted MSD was evaluated according to the evidence-based guidelines, and its statistical significance was tested only if it had clinical significance, which not only decreased the risk of chance findings but also ensured the clinical relevance of the results. Additionally, the nationwide population-based longitudinal study design facilitated the generalizability of the findings.This study also has some limitations. First, because the OSCAR study focuses on patients who have survived for at least 1 year after esophagectomy, we measured dispositional optimism at 1 year post-surgery and not at time of cancer diagnosis or surgery. The observed predictive effect of dispositional optimism on HRQL should be interpreted in light of the assessment time point, even though dispositional optimism remains relatively stable over time and across stressful situations including receiving cancer diagnosis and surgery,In conclusion, this study showed that higher dispositional optimism predicted better HRQL at 1, 1.5, and 2 years post-surgery in several aspects among patients with esophagectomy for cancer. The predictive value of dispositional optimism may help identify high-risk patients with poor HRQL recovery after esophageal cancer surgery, leading to timely and tailored interventions to patients in need, and therefore contribute to the improvement of postoperative HRQL and probably even survival.Supplementary file1 (DOCX 32 KB)Below is the link to the electronic supplementary material.


Vulvodynia and pudendal neuralgia comprise significant contributors to vulvar‐related pain and its impact on daily life.A retrospective clinical audit was conducted at the Women’s Health & Research Institute of Australia, Sydney, to determine the pattern of use and the efficacy of the application of topical amitriptyline 0.5% plus oestriol 0.03% in organogel (AOO), to the vulvar vestibule in reducing the impact of pain on daily life.There were 1174 patients who received a script from May 2017 until February 2020: 1054 patients agreed to be contacted and had a valid email address.There were 376 (35.7%) patients who replied. Pain with intercourse was the main indication for use. Treatment was rated effective by 51.2% (95% CI: 35.4–66.8%) of patients less than 30 years of age, 66.7% (95% CI: 57.3–74.9%) of patients 30–50 years of age, and 58.3% (95% CI: 50.9–65.4%) in patients over 50. Stinging at the site of application was the most commonly reported side effect.Topical AOO is an effective and well‐tolerated treatment for vulvar pain. The impact of vulvodynia and pudendal neuralgia can be significant on a woman’s quality of life, affecting her mental health, intimacy, and activities of daily living both socially and occupationally. Dyspareunia is a common and debilitating condition with a prevalence up to 39.5%. Vulvodynia has an estimated lifetime prevalence varying between 8% and 28%.Although the pudendal nerve does not innervate the bladder or bowel directly, neurogenic inflammation likely contributes to cross‐sensitisation resulting in the wide spectrum of symptomatology in both vulvodynia and pudendal neuralgia. Ongoing peripheral input at the shared sacral dorsal root ganglions results in release of neurotransmitters and peptides including substance P, calcitonin gene‐related peptide and nerve growth factor in adjacent pelvic structures.Management of vulvodynia and pudendal neuralgia should be individualised to each patient with current evidence supporting the role for oral antidepressants, anticonvulsants; topical preparations of anaesthetics, oestrogen, corticosteroids and pudendal nerve blocks. Non‐pharmacological treatment plays an equally important role and can comprise of physical therapy including nerve glides, pain education and lifestyle modifications such as loose clothing and standing desks.et al. assessed the use of topical amitriptyline 2% in sorbolene cream with 33.9% of patients positively responding to treatment.et al.Targeted therapy with topical compounded ointments or creams has the benefit of reduced systemic side effects while concurrently avoiding interpatient variability with oral dosing regimens.® .AOO consists of amitriptyline 0.5% and oestriol 0.03% in organogel. This amounts to 5 mg and 0.3 mg per mL of gel respectively. An organogel was chosen as the base, because of its amphiphilic properties. The recommended dose is 0.5 mL applied to the vulva once or twice a day. The maximum daily dose is therefore 5 mg of amitriptyline and 0.3 mg of oestriol. These present as low doses compared to topical or oral medications currently commercially available. The premise for its use focuses on symptomatic treatment of vulvo‐vaginal pain, irrespective of aetiology, through reduction of the sensitivity of the mucosa by the membrane stabilising effect of amitriptyline. Additionally, the stimulatory effect of oestriol promotes increased mucosal regeneration, flexibility and lubrication.Ethics approval to contact patients suitable for clinical audit was obtained . A search of our clinical records system identified patients who were issued a script for AOO from May 2017 to February 2020 by their treating physician. Of the 1174 females identified, 1127 individuals had previously consented to being contacted for research purposes. Of these, 1054 with valid email addresses were invited to complete the survey.A single electronic survey to obtain demographic data and outcome measures including the validated Pelvic Pain Impact Questionnaire2 test statistic was used to compare categorical data with statistical significance threshold of P < 0.05. Where the null hypothesis was rejected, post hoc comparisons were made by examining the standard residuals after adjusting the critical z‐score value per the Bonferroni method. Logistic regression was performed on dichotomous outcome . Ordinal logistic regression was used to model the association of side effects and duration of use.The χP = 0.66) with a smaller representation of the less than 30 years old in the audit sample , with an equivalent greater representation of the over 50 years old group . Of the 376 respondents, 47 (12.5%) reported vaginal mesh problems, which is statistically consistent with the proportion in the total cohort with mesh .Women invited to participate in the audit ranged from 18 to 89 years of age. A total of 376 out of 1054 responded to the online survey (35.7% responder rate). Incomplete responses to individual questions were removed from data analysis resulting in variable total counts for each question. The age distribution of the survey respondents compared to the cohort was equivalent in the 30–50 group (Respondents were asked to indicate their duration of use ranging from short term use up to 3 months), to ongoing (>12 months) use  followed by pain with sitting (124/376 = 33.0%), bladder issues (76/376 = 20.2%) and vaginal mesh problems (47/376 = 12.5%). Some patients mentioned more than one reason for use of AOO. Women self‐reported AOO to be beneficial across all age groups , keeping constant the reason for use.Ninety of the 376 24.0%) patients reported one or more side effects (Table .0% patieReversibility was noted in 53% of patients with resolution of side effects on cessation of AOO.Within the limitations of a retrospective audit, the results indicate that AOO is beneficial in the treatment of pudendal neuralgia type symptoms related to a variety of aetiologies.et al.,et al.The lower response rate to the audit in the younger age group is a commonly observed phenomenon. In a study conducted by Eaker et al., for instance, noted a 34–56% positive response rate when using amitriptyline 2% in sorbolene cream for the management of patients with entry dyspareunia; 10% of these patients reported complete resolution of pain.There were 64.4% of respondents who reported an improvement in vulvar pain during intercourse, also known as entry dyspareunia. This positive response compares favourably with the use of other topical preparations. Pagano Typical adverse effects of amitriptyline with oral administration most commonly include drowsiness, dizziness, dry mouth and constipation among other anticholinergic effects. Topical administration carries the benefit of increased local tissue uptake rather than systemic, theoretically reducing the side effect profile.Based on the results of this audit, a prospective randomised placebo‐controlled study has been designed to further qualify the efficacy of AOO for the treatment of entry dyspareunia.


Results of the most commonly used inguinal hernia repair techniques often originate from expert centers or from randomized controlled studies. In this study, we portray daily-practice results of a high-volume, regional surgical group in the Netherlands, comparing TREPP (open (posterior) transrectus sheath pre-peritoneal) with Lichtenstein (open anterior) and TEP (endoscopic (posterior) totally extraperitoneal). We hypothesize that the TREPP shows more favorable outcome compared to the current gold standard procedures: TEP and Lichtenstein.Between January 2016 and December 2018, 3285 consecutive patients underwent surgical treatment and were included for analysis. The outcome measures were postoperative pain, recurrence rate and other surgical complications. Propensity-score matching was used to address potential selection bias.p = 0.67) nor in TREPP compared to TEP . There was no statistically significant difference in recurrences in the TREPP group compared to Lichtenstein , nor in the TREPP versus TEP comparison After propensity-score matching, there was no statistically significant difference in postoperative pain in the TREPP group compared to the Lichtenstein group (TREPP 7.3% versus Lichtenstein 6.3%; This study compares TREPP with Lichtenstein and TEP in the presence of postoperative pain, recurrences and other adverse outcomes. After propensity-score matching, no statistically significant difference in postoperative pain or recurrences remained between either TREPP compared to Lichtenstein, or TREPP compared to TEP. Based on these results, TREPP, Lichtenstein and TEP showed comparable results in postoperative pain, recurrences and other surgical site complications. Inguinal hernia repair is one of the most frequently performed surgical procedures worldwide with up to 20 million patients annually . In the In the current guidelines, the preferred surgical technique in any elective inguinal hernia repair depends on many different characteristics and can differ between patients. In general, a surgical technique that includes mesh to strengthen the abdominal wall is recommended . The totTEP and Lichtenstein show similar perioperative complications and operating times . After tFor the Lichtenstein technique, prevalence varies up to 29% , 8–10. AMost results originate from high-volume expert centers where one specific technique is used or from randomized studies that usually include a specific subset of the general population. The cumulative results of these specific studies have become the textbook-outcome results but may differ from the general daily practice. In this study, we portray daily-practice results of inguinal hernia surgery performed in four high-volume regional hospitals in the Netherlands, both teaching and non-teaching, on TREPP, TEP and Lichtenstein. The aim of this study is to evaluate textbook-outcome results on inguinal hernia surgery in the daily practice in regional hospitals, to provide both doctors and patients with more insights on the risk of complications after inguinal hernia surgery. We hypothesize that TREPP results in a more favorable outcome  compared to the gold standard procedures TEP and Lichtenstein.The Medical Ethics Committee of our institution  confirmed that this retrospective study could be carried out without the need for ethical review, and the institutional boards of the four hospitals approved the execution of the study without the need for consent in accordance with Dutch regulations. All participating centers provided data of experienced hernia surgeons  performing or supervising the surgical treatment. The aim of this study was to evaluate the daily practice in inguinal hernia surgery in four teaching and non-teaching hospitals in the northern region of the Netherlands. The primary outcome of the study was to evaluate the development of postoperative pain. The secondary outcomes are surgical site occurrences .All patients with a primary or recurrent, direct or indirect, inguinal or femoral hernia, in an acute or elective setting were included in the database. Patients who did not undergo surgical treatment were excluded from the database. Patients were operated with different anterior or posterior techniques, e.g., Lichtenstein, TEP, TAPP, TREPP, TIPP, Bassini, Shouldice, Stoppa, Rutkow-Robbins, Fabricius. The choice of technique was dependent on the surgeon and on whether or not it concerned a primary or recurrent hernia. For this study, analyses were performed on all adult male patients with primary, unilateral inguinal hernia, who were treated in the elective setting.Patients were scheduled for regular follow-ups at the outpatient clinic at two–six weeks postoperatively. More visits were scheduled only in case of adverse events. Every outcome that was mentioned in the electronic patient file was noted in the database. For postoperative pain specifically, patients scored a “yes” if they: visited the outpatient clinic after a regular follow-up because of inguinal pain; received pain treatment or had any further pain evaluation .To address potential selection bias due to the observational nonrandomized study design, we implemented propensity-score matching to achieve a more balanced study cohort. In this, patients treated with TREPP were 1:1 matched to patients treated with Lichtenstein, using their probability to receive TREPP, i.e., the propensity score for TREPP. Matching was performed with a 0.01 maximum allowed difference in the exact propensity scores in a ‘pair of patients’ treated with TREPP and Lichtenstein. Propensity score of individual patients was estimated using multivariable logistic regression with covariates describing condition at baseline. In addition, patients treated with TREPP were matched to TEP used the same procedure.Subsequent analyses were performed using the matched cohorts. Percentages of outcome were calculated and exact odds ratios with 95% confidence intervals estimated. For this, exact conditional logistic regression was used to control for potential lack of independence due to matched pairs.p values less than 0.05 were considered statistically significant. Statistical analysis was performed with SAS 9.2 .Baseline characteristics between groups were analyzed using Chi-square test and a two-tailed Fisher exact test. Outcome measures in both cohorts were analyzed using a two-tailed Fisher exact test. In the period between January 1st, 2016 and December 31st, 2018, a total of 3762 inguinal hernia repairs were performed. Surgeries were performed in four regional hospitals, one teaching and three non-teaching. The flowchart of selected patients for analysis in this study is shown in Fig. n = 398) was younger  than the Lichtenstein cohort (n = 1051). The TEP cohort (n = 552) had the lowest mean age . Baseline patient characteristics are shown in Table Before propensity-score matching (PSM), the cohort undergoing the TREPP procedure (p = 0.022). There was no significant difference in the number of recurrences in both cohorts  The cumulative number of other adverse outcomes  was significantly higher in the Lichtenstein cohort (13.0%) as compared to the TREPP cohort . These numbers are shown in Table The presence of postoperative pain in the Lichtenstein cohort (before PSM) was significantly lower than in the TREPP cohort  could be paired with a patient undergoing the Lichtenstein procedure, which created two groups with a total of 796 patients. The mean age of the non-matched group was significantly higher than the mean age in the matched pair group . The ASA-classification was significantly higher in the non-matched group (p < 0.001). When comparing TREPP versus Lichtenstein after PSM, the patients undergoing the TREPP technique did not experience significantly more postoperative pain as compared to the Lichtenstein group . The percentage of recurrences in the TREPP cohort was 3.8%, which did not differ significantly compared to the Lichtenstein cohort . The total number of adverse outcomes did not significantly differ between the two groups . The odds ratio after exact conditional logistical regression for postoperative pain was 1.2  0.65–2.14; p = 0.67), for recurrence 1.5 , for combined number of other adverse outcomes 0.7 . These results are shown in Table When comparing TREPP with Lichtenstein after PSM, all patients undergoing the TREPP procedure n = 98 could p = 0.17) and the prevalence of recurrent inguinal hernia in the TEP cohort was 2.5% . The cumulative total number of other adverse outcomes did not differ significantly between the two groups . The results of TREPP versus TEP before PSM are shown in Table Prevalence of postoperative pain in the TEP cohort did not differ significantly compared to the TREPP procedure . Furthermore, there was no difference in ASA-classification between both groups (p = 0.29). When comparing the TREPP to the TEP after PSM, no significant difference was present  in the presence of postoperative pain. Recurrences occurred in 3.9% of TREPP procedures versus 2.8% recurrences after the TEP procedure (p = 0.55). The cumulative total number of other adverse outcomes did not differ significantly . The odds ratio after exact conditional logistical regression for postoperative pain was 1.9 , for recurrence 1.4 , for combined number of other adverse outcomes 0.9 . The results of TREPP versus TEP after propensity score matching are shown in Table When comparing TREPP to the TEP technique after propensity-score matching, 390 pairs could be matched on propensity scores. This created two groups of a total of 780 patients. The non-matched group that remained  was significantly younger than the matched group  with the two most performed elective unilateral inguinal hernia repairs: Lichtenstein and TEP, recommended by international guidelines on inguinal hernia. We performed a propensity-score-matched (PSM) analysis to lower the potential treatment selection bias known to exist with retrospective cohorts, comparing both TREPP with Lichtenstein as well as TREPP with TEP. After PSM, there was no statistically significant difference in the presence of postoperative pain when comparing TREPP with Lichtenstein or TEP. The odds ratios for postoperative pain of 1.2 (Lichtenstein) and 1.9 (TEP) seem to show a tendency in favor of TEP, but there was no statistically significant difference. There was also no statistically significant difference for recurrences or cumulative other outcome measures.When considering the overall percentages of postoperative pain for these three procedures, there is a remarkably low prevalence of postoperative pain especially in all patients treated with the Lichtenstein procedure (4.2%) (after matching 6.3%). In the available literature, this number varies from 21.7 to 29% , 8, 10. We investigated the differences in groups before and after propensity-score matching. It appeared that the unmatched patients in the TREPP–Lichtenstein comparison were all Lichtenstein patients, mostly of older age and higher ASA classification. It seems that this group of patients experience less pain than younger patients . A possiA possible explanation for the relatively low percentage of postoperative pain in the Lichtenstein population in the regional (teaching and non-teaching) hospitals included in this study is the high level of experience with this technique.The results of this study should be interpreted cautiously. The retrospective nature of this study prevents certainty of follow-up of every patient. The authors attempted to register the number of patients with pain as accurately as possible, by purposely not using the definition of chronic postoperative inguinal pain (CPIP: pain > 3 months after surgery) . Rather,The theoretical low percentages of pain following the TREPP procedure, as seen in previous cohorts , 13 was Considering the results as well as the inherent potential biases, this study does not show significant differences between both TEP/Lichtenstein (gold standard procedures) and the TREPP procedure. The authors recommend a well designed randomized controlled clinical trial comparing the TREPP to either the TEP or the Lichtenstein to confirm the results from this study. Should the results be confirmed, however, the TREPP could play an important role in the decision-making for inguinal hernia repair. As an example, TREPP could play a useful part in recurrent hernia repair after previous anterior approach. Until now, the standard concept for treatment of recurrence after anterior approach is a posterior approach, mostly leading to a TEP (or TAPP) procedure. If the results from this study are indeed an accurate representation of the outcome, the TREPP procedure could take part in this flow chart, with possible advantages such as: single-incision access viable for intra-peritoneal inspection, pre-peritoneal location of mesh, possibility of regional anesthesia and potential lower costs due to the fact that laparoscopic equipment is not needed.


It is of interest to evaluate a single dose of three different analgesics compared to placebo in patients with symptomatic irreversible pulpitis. 120 patients were enrolled with severe pain in this prospective clinical trial. Patients were randomly dividedinto four groups after shaping and cleaning of root canals. This includes placebo, piroxicam 20mg, acetaminophen 325mg with aceclofenac sodium 100mg and acetaminophen 650mg. Participants were given a questionnaire to note the pain scores at various time intervals along with the respective tablets in a concealed manner. Data thus collected was analyzed for statistical significance. The severity of pain decreased in all the three interventional groups compared to the control group (p <0.01) at6 hours. Zerodol-P and dolonex showed better pain reduction in comparison to the placebo and dolo 650 group (p <0.05) at 12 and 24 hours. Data shows that both zerodol-P and dolonex groups had similar effects at all time intervals. Thus, a single dose ofanalgesic such as Zerodol-P and Dolonex following shaping and cleaning of root canals relieved pain at all time intervals of the treatment. However, Dolo 650 performed better during the initial 6hrs after completion of the shaping and cleaning of root canalscompared to the placebo. Pulpitis can be defined as the inflammation of the pulp mainly due to cariogenic reasons and less often due to trauma and restorative treatment. Kim et al 1990) described this process of inflammation of the pulp 990 descr. Ng et aOne hundred and twenty patients enrolled for this prospective clinical trial, which was endorsed by the institutional ethical committee (IHEC/SDMDS11ODS7). The sample size was determined based on a pilot study of 40 cases (10 per group), using G Power 3.1.2version, and details as follows: power of 0.9 and p<0.05, the sample size arrived were 27 per group, for the compensation of drop outs during follow-up, sample size was set at 30 per group. The criteria for the enrollment as follows: Patients aged from 18-45years with no medical problems, no history of medication used 12 hrs prior to presenting for the treatment, patients with irreversible pulpitis with no signs of apical periodontitis, patients with severe pain (7-10) in 10 points visual analog scale. The pulpalstatus of the affected tooth was subjected to sensibility testing . Patient with one tooth of irreversible pulpitis with severe pain was selected for the clinical trial. Informed consent was taken from all the participants.A trained person carried out randomization before the beginning of the trial, using a table of random numbers with block sizes being unknown to the investigators. SNOSE  method was employed for the allocationconcealment. A piece of paper containing a randomized number was sealed in the opaque cover containing the serial number, which was done by a person who was not associated in this trial. The sealed envelope was opened once the intervention was assigned. Theenrolled participants were divided randomly into 4 groups respectively; Group 1 - Placebo (gelatin capsule) Group, Group 2 - Dolonex , Group 3- Zerodol-P , Group 4 - Dolo 650 . The preoperative and postoperative pain scores were recorded using 10 points visual analog scale (VAS), No pain (Score - 0), Mild pain (Scores 1-3), ModeratePain (Scores 4-7), Severe pain (Scores 7-10).The principal investigator following standard protocol performed treatment in all cases. Patient consent was obtained and the tooth was anesthetized using 2% lignocaine with 1:200000 epinephrine solution, followed by standard access cavity was prepared underrubber dam isolation and the occlusal reduction was done. The length of all the canals was measured by an electronic apex locator  and verified using radiographs. Root canal preparation was done in a crown down manner usingNi-Ti rotary instruments . All the canals were instrumented till size 25 of Ni-Ti rotary instruments 0.5mm short of working length. Copious irrigation was done using 3% Sodium Hypochlorite solution  and 17% Ethylenediaminetetraacetic acid (EDTA)  to facilitate the instrumentation. Canals were dried using paper points and the access cavity was sealed with temporary restorative material using Cavit . A single dose of interventional drug was given for the respective patients, along with a rescue medication of Ketorolac 10mg , was given at the end of first visit and the patient was instructed to call up the evaluatorbefore taking the tablet.A questionnaire containing a pain scale (VAS) was given after the treatment to record the intensity of pain at 6, 12 and 24 hours respectively. At the end of this trial endodontic treatment was completed.Normal Distribution data assessment was done by the Kolmogorov- Smirnov test. The obtained values were analyzed statistically using one-way ANOVA comparing baseline and the other time periods. Independent t-test was done to assess the performance of all drugsat all time intervals  using SPSS 20 .Over a period of 19 months, 120 participants were selected upon receiving the informed consent for the study. The demographic data were reported. Totally 5 patients did not take into account: 2 from Placebo, 1 each from the other three groups. The reason wasthey had taken a rescue medication as they experienced severe pain . The AnaIn this prospective controlled trial we chose three different analgesics to assess the pain reduction following shaping and cleaning of root canals in patients with symptomatic irreversible pulpitis. Only patients presenting with severe pain VAS >7-10)were enrolled. Controlling this pain is often a difficult task for the clinician. The endodontic treatment was performed in a crown down manner, the advantages are- less extrusion of debris thereby having less postoperative pain, reduction of microorganismspushing towards apical areas, easier smear layer removal with the help of chelating agents, enhanced disinfection of the entire canals thereby facilitating the irrigant flow . ProTapewere enrWe used three different analgesics in comparison to placebo. The results showed that a single dose of analgesic such as Zerodol-P and Dolonex for shaping and cleaning of root canals relieved pain at all time intervals of the treatment. However, Dolo 650performed better during the initial 6 hrs after completion of the shaping and cleaning of root canals compared to the placebo.


Physical activity has been shown to improve quality of life in cancer patients with some evidence in multiple myeloma. This study aimed to determine myeloma patients’ exercise levels, their perception of physical activity, and to explore correlations with quality of life. Myeloma outpatients were invited to complete a number of questionnaires, including the Godin leisure-time exercise questionnaire (GLTEQ) to determine their exercise levels, the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire to assess health related quality of life, and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire to assess fatigue.Of the 65 respondents, 75% would like to increase their exercise level. Weakness, fatigue and pain were the most commonly perceived barriers to physical activity. 59% would like to receive physical activity advice. Only 25% were deemed active based on their GLTEQ scores. Finally, there was a significant positive correlation between the GLTEQ score and the FACT-G score (p < 0.001). Results highlight an unmet exercise need in myeloma patients. Current practice should be reviewed to develop a more holistic care model that incorporates tailored exercise advice or programme.The online version contains supplementary material available at 10.1186/s13104-021-05591-y. Multiple myeloma (MM) is an incurable bone marrow malignancy with multiple relapses and remission periods, followed by eventual treatment resistant disease. Recent novel therapies have dramatically improved patients’ survival. MM survivors now face the challenge of regaining premorbid psychosocial and physical wellbeing, whilst coping with disease symptoms and treatment side effects. With osteolytic bone destruction occurring in nearly 90% of patients , physicaPA has been shown to associate with less fatigue, improved QoL and physical functioning in cancer patients –5. PreviPA is recognised as an important aspect to the quality of cancer patients’ survival. The U.K. Independent Cancer Taskforce recommended that all cancer patients should receive tailored PA advice. In MM, such an initiative remains hampered by a lack of understanding and awareness of the benefits of PA, and how to promote safe exercise in the context of myeloma bone disease. We sought to find out MM patients’ attitude towards PA and ascertain their levels of PA and QoL in order to better understand their survivorship needs.This is a service evaluation study conducted in the University College London Hospital, a tertiary myeloma centre. Patients attending MM outpatient clinics were invited to complete a survey  , 9. A scCompletion of this survey was optional and implied consent was obtained when patients returned the completed survey. All responses were anonymised. NHS Health Research Authority (HRA) ethics approval was not required based on the HRA decision tool  and the Between March and May 2019, 65 patients completed the survey. Patient characteristics are shown in Table Fifty-nine percent would like to receive PA advice from a HCP. The three most selected options to receive such advice were written leaflets (29%), a face-to-face session with a HCP (28%) and verbal advice in clinic consultation (23%). Other chosen methods include a telephone call from a HCP (14%), mobile application (12%) and internet website (11%). None of them chose group seminar.Our respondents had a median GLTEQ score of 15 (range 0–66). According to their scores, 25% were deemed physically active, 17% moderately active and 39% inactive. Thirteen (20%) did not specify their PA level. The median FACT-G score was 73.1 , and the median FACIT-F score of 32.5 . GLTEQ, FACT-G and FACIT-F scores were not significantly different between males and females, and between those on or off myeloma treatment. Nor did these scores correlate with years since myeloma diagnosis, or with numbers of prior treatment lines , and also between GLTEQ and FACIT-F scores   . These lIt is also noteworthy that while most patients had low exercise levels, the majority would like to improve this. This suggests an awareness of the possible benefits of exercise, and an unmet survivorship need. Over half of patients wished to receive PA advice from a HCP, suggesting that one of the barriers to exercising may be lack of confidence to do so safely. This echoes themes reported in existing literatures , 7, wherFatigue is a ubiquitous problem in cancer patients. In MM, it is compounded by the use of steroids in almost every treatment line, bone pain and fractures, and the autonomic neuropathy that accompanies many anti-myeloma drugs. Our patients had a lower mean FACIT-F score than that of the general population (32.5 versus 43.6) . Almost We observed that higher PA levels were associated with better QoL, in accordance with previous studies –5. AlthoMM patients have lifelong follow up in outpatient clinics, where emphasis is often placed on myeloma biochemical markers rather than patients’ survivorship needs. Our study results highlight an unmet need to develop a more holistic care model, in which PA is assessed and promoted appropriately, with professional support from physiotherapists as appropriate. It is also important to identify and address barriers to PA proactively, such as through pain and neuropathy management. In line with MM supportive care guideline , regularA more formal way to promote PA is to deliver supervised exercise programmes, which, when administered by specialist personnel with appropriate screening procedures, have been shown to be safe and feasible . SpecialResults are limited by the cross-sectional nature of this single-site study, and by small sample size.Self-report data is subjected to bias and limitations such as introspective ability and interpretation of questions.Associations demonstrated in the study have no causal relationship due to its design.Additional file 1. Physical activity survey.


Although non‐suicidal self‐injury (NSSI) disorder is highly prevalent in adolescents, its relationship with pain system function and suicidality is still controversial. The present study was designed to assess the function of the nociceptive afferent pathways and the endogenous pain modulation in adolescent patients with NSSI and to longitudinally register any suicide attempt, describe its frequency and find a possible association between suicide, neurophysiological measures and psychological measures.We enrolled 30 adolescents suffering from NSSI and 20 age‐ and gender‐matched healthy controls. Patients underwent a comprehensive psychological evaluation. Each participant underwent thermal pain thresholds of the quantitative sensory testing, laser‐evoked potential recording to study the ascending nociceptive pathway and the conditioned pain modulation testing to test the endogenous pain modulation.We found that patients with NSSI had a reduced amplitude of the N2 component of laser‐evoked potentials and an abnormal conditioned pain modulation. The amplitude of the N2 was associated with suicidal risk.The deficit of the endogenous pain modulation likely depends on a saturation due to continuous pain solicitation. The strong association of a reduced amplitude of the N2 component with suicide suggests that it may serve as a possible biomarker in self‐harming adolescents.The present study identifies the N2 component of laser‐evoked potentials as a possible neurophysiological biomarker of suicidal risk in patients with non‐suicidal self‐injury, therefore, raising the possibility for a non‐invasive test to identify subjects at higher risk of suicide among self‐harming patients. We then longitudinally a) described the prevalence of suicide in our population, b) identified two distinct populations of patients  to compare their neurophysiological and psychological data, collected in the first part of the study and c) assessed the presence of any predictive factor for suicidality among the variables recorded during the study.22.1N = 9), aripiprazole (N = 6), selective serotonin reuptake inhibitors (N = 4), no drugs (N = 11).We consecutively screened 42 patients and enrolled 30 patients (12 patients and/or their guardians declined to participate) with NSSI diagnosed within 5 years from the symptoms onset  with five or more self‐injurious behaviours without suicidal intention occurred in the last year. Patients were consecutively recruited among the inpatients of the Adolescent Unit of the Child Psychiatry Department of the ‘Sapienza’ University. As a standard assessment procedure, all subjects were interviewed and screened for DSM‐5 diagnoses with the Italian version of the Schedule for Affective Disorders and Schizophrenia for School‐Age Children/Present and Lifetime Version  was recruited among patients’ friends and relatives.Each subject underwent a comprehensive evaluation of the pain system function by (1) static psychophysical measures of sensory and pain thresholds for the nociceptive system evaluation, using quantitative sensory testing (QST) and laser‐evoked potentials (LEP) and (2) dynamic psychophysical measures to evaluate the endogenous pain modulation, using the conditioned pain modulation (CPM) testing.All procedures took place at the Department of Human Neuroscience of Sapienza University Rome, in accordance with the Declaration of Helsinki. This research was approved by the local institutional review board (Prot. n 278/16 RIF.CE: 4007) and all patients and their guardians gave their informed consent.2.2Each NSSI patient was evaluated with the following psychopathological measures, extensively described in previous works: Deliberate Self‐Harm Inventory (DSHI) Gratz, , Repetit2.3For quantitative sensory testing, we used a thermode . The computer‐driven PATHWAY system contains a metal contact plate (contact area 30 × 30 mm) equipped with an external Peltier element that cools and heats the plate to target levels. The baseline temperature of 32°C reached target temperature at a ramp rate of 1°C/s. Quantitative sensory measures were tested on the right‐hand dorsum. In all patients, we tested the cold detection threshold (CDT), the warm detection threshold (WDT), the cold pain threshold (CPT) and the heat pain threshold (HPT). All procedures took place in accordance with the recommendations given by the German Research Network on Neuropathic Pain  laser   signals were simultaneously recorded using surface electrodes.https://www.letswave.org). Continuous EEG data were bandpass filtered, with a Butterworth filter, from 1 to 30 Hz for analysis in the time domain. EEG epochs were extracted using a window of 1,500 ms  and baseline corrected using the prestimulus interval. Trials contaminated by eye blinks and movements were corrected using an independent component analysis algorithm , consisting of two 30 × 30 Peltier thermode, one used as test stimulus and the other as conditioning stimulus.CPM was performed using a parallel paradigm  a conditioning heat stimulus lasting 60 s, using the same stimulation temperature of the test stimuli. During the last 30 s of this conditioning stimulation, two “test stimuli” were repeated consecutively on the non‐dominant forearm, and their intensity rated. The CPM effect was calculated as the difference in the average pain scores of the mean rating of the conditioned and unconditioned ‘test stimuli’. A negative value indicates intact CPM  between subgroups  with post hoc multiple comparisons and false discovery rate (FDR) correction.A preliminary analysis of association was performed by evaluating group differences (controls versus. NSSI cases and attempted vs. non‐attempted suicide) with the Mann–Whitney test or unpaired Student's Moreover, since we considered a wide set of explanatory variables, capturing multiple aspects of participants’ clinical condition that can possibly affect the outcome of interest, the predictors which contribute to measure common traits of the individual status were naturally expected to form clusters of highly correlated factors. This phenomenon, known as multicollinearity, imposed the adoption of variable selection criteria to avoid information redundancy and unreliable estimates of the predictive value of the single covariates .All tests performed in the analysis were two‐sided and a 33.1The average age was 15.7 years (11–18) for patients and 16.8 years (11–18) for controls. The average duration of illness was 19.9 months (1–60).Within 2 years, 16 patients attempted suicide (53.3%).3.2Results from univariate analysis are summarized in Table The comparison of QST data between patients and control group was not significant for any of the variables explored Table  Figure . In the p < 0.04; p < 0.006).The N2 amplitude of laser‐evoked potentials and the CPM effect significantly differed between patients and controls ; the CPM protocol therefore yielded a value around 0 (−0.9), thus indicating a deficit in the descending inhibitory pain control , which resulted increased in the suicidal group. The N2 component of laser‐evoked potentials was significantly lower in suicidal patients than in non‐suicidal  and non‐suicidal versus suicidal (p < 0.02), while no significant difference was found between control versus non‐suicidal (p > 0.5)  of the N2 amplitude between groups  disclosed a significant difference between control versus suicidal  Figure .p < 0.04) and control versus non‐suicidal (p < 0.004), while no significant difference was found between suicidal versus non‐suicidal (p > 0.3)  of the CPM variable between groups  disclosed a significant difference between control versus suicidal  Figure .3.6p = 0.036). Specifically, the negative estimated coefficient indicated that lower LEP N2 amplitude values in NSSI patients are associated with an increased suicide risk. A borderline result emerged for the effect of the severity class of the NSSI (p = 0.062) evaluated through the CRS‐NSSI.Through the multicollinearity analysis , we specified a logistic regression model with 10 potential predictors of the suicidal risk. The optimal model in terms of Akaike information criterion value was identified with backward selection procedure and the corresponding estimates are shown in Table Several goodness‐of‐fit tests were applied to the estimated logistic model (Table S2); they all provided evidence in favour of the model adequacy to the observed data.p < 0.001) as well as appreciable SE = 75% and SP = 93%. Additionally, the sum of SE and SP is manifestly above 1, namely 1.679, confirming a global good predictive power. PPV and NPV values were, respectively, 92% and 76%.The overall performance of the model to predict the outcome was explored with the ROC curve Figure  and the p < 0.001). The optimal threshold was 14 (µV), corresponding to SE = 69% and SP = 71%. PPV and NPV were, respectively, 73% and 67%.The accuracy of the sole LEP N2 amplitude value as a biomarker of suicide was also investigated with the construction of the corresponding ROC curve reported in Figure 4Our findings disclosed an abnormal pain modulation in patients with NSSI and a reduced amplitude of the N2 component of laser‐evoked potentials. The latter should be regarded as a potential biomarker of suicidal risk.4.14.1.1The findings of normal thermal pain, laser pinprick thresholds and pain ratings in our patients, compared to healthy subjects, are in contrast with previous studies in patients with self‐injurious behaviours associated with borderline personality disorder (BPD) that had used the cold pressor test . However, the study was conducted in a cohort of adult patients with self‐injury behaviour associated with a defined personality disorder (BPD), therefore not comparable with the adolescent population of our study, diagnosed with NSSI alone. Furthermore, a more in‐depth analysis of our data disclosed that the subgroup of patients with attempted suicide significantly weighted on the difference between patients and controls and that the non‐suicidal population behaved like controls Figure . Since t4.1.2The CPM disclosed a deficit of the endogenous pain modulation in patients with NSSI. The lack of function of the endogenous system seems not to validate the interesting hypothesis proposed by Magerl and colleagues , suggestAnother interesting explanation to our results concerning the CPM deficit should be sought in the theory proposed by Schmahl and Baumgärter  to expla4.2The chance to follow our patients for more than 2 years allowed us to register the incidence of attempted suicide and, more importantly, to isolate any biological variables among the ones collected that would allow us to distinguish NSSI from a self‐injury behaviour prodromal to an attempted suicide.4.2.1The psychopathological instruments used in the study did not clearly distinguish between suicidal and non‐suicidal patients. A recent meta‐analysis on the correlates of suicide attempts (SA) among self‐injurers , proved to be a weak predictor of suicide: patients with grade 3 and 4, namely those with moderate to severe grade of NSSI, had a higher risk of suicide attempt during the study period.p < 0.1). Although elevated hopelessness can be considered a common trait to all self‐harming, many authors pointed out its predictive role for suicide (Klonsky et al. The Bech Hopelessness Scale, evaluating the presence and degree of Hopelessness resulted increased in suicidal patients as compared with non‐suicidal (Regarding Personality inventory data, we found that three subfacets approached significance: anhedonia, impulsivity, risk‐taking. The anhedonic trait has been observed in subjects with suicidal behaviour including adolescents (Brausch & Gutierrez, Several studies have also reported impulsivity and risk‐taking traits as predictors of suicidal attempt especially among adolescence, where completed suicide often occurs suddenly, unexpectedly and impulsively (Brodsky et al. In light of the results of PID‐5 and clinical assessment, our sample does not seem to show a clear trajectory oriented towards BPD, thus suggesting that NSSI may have a significant clinical and diagnostic heterogeneity and is not just an expression of underlying or prodromal BPD. It is, therefore, important to recognize NSSI as an independent diagnosis with peculiar features.4.2.2The most interesting data we obtained are the presence of a significant reduction of the N2 component of laser‐evoked potentials’ amplitude in subjects who attempted suicide compared to subjects who maintained a non‐suicidal self‐injury behaviour. This finding was further supported by an accurate multivariate analysis which found the LEP N2 amplitude variable to be the only statistically significant predictor of suicidal risk with lower N2 amplitude values in NSSI patients associated with an increased probability to attempt the suicide.The N2 component of laser‐evoked potentials generated at the level of the anterior cingulate and of the anterior mid‐insula (Garcia‐Larrea, Indeed, previous functional neuroimaging and post‐mortem studies in patients with suicidal behaviour (see van Heeringen & Mann, On the other hand, both the lateral and medial pain systems have been shown to be dysfunctional in patients with major psychiatric disorders associated with psychosis (Minichino et al. Given these considerations, it is possible that the N2 component of laser‐evoked potentials could represent an unspecific measure of salience circuit dysfunction and, therefore, not a specific biomarker for suicide, but rather an index of impairment of subjective evaluation of one's affective state and of internalization of perceptions of oneself by others, a common finding in several psychiatric disorders (New et al., However, a biomarker can demonstrate good clinical utility because it is able to stratify patients into clinically meaningful categories, with a high sensitivity and specificity, without directly reflecting the mechanisms that give rise to a given clinical condition, as the patterns of neural activation that allow discrimination between conditions might be entirely epiphenomenal (Mouraux and Iannetti Although not specific, the amplitude of the N2 may be considered a candidate biomarker due to the rapidity and the non‐invasiveness of the examination and the good sensitivity in identifying a population at risk among self‐harming adolescents. The area under the curve of ROC disclosed a sensitivity around 70% below a cut‐off of 14 μV.4.3The results of this study should be considered in the light of several limitations. First, the lack of information about the reproducibility of our findings: Further studies are needed to confirm the N2 reduction in suicidal patients among adolescent self‐harmers. Without replications, the potential role of the N2 component as a biomarker of suicide cannot be determined. Second, we cannot rule out the possibility that the medications used by NSSI patients affected the results obtained (Mucci et al. 5Our findings indicate that NSSI is associated with an abnormal pain processing not related to an over function of the endogenous pain control, which, on the contrary, shows a dysfunction possibly resulting from a saturation due to the repetition of self‐injurious behaviours. Among NSSI patients, the amplitude of the LEP N2 component could be a candidate biomarker for suicide, even stronger when associated with a high severity of disease assessed by the CRS‐NSSI.Further studies are needed to replicate our data and test for specificity. Since the presence of this neurophysiological alteration in adolescents with onset of NSSI behaviours offers the chance to use a non‐invasive test to identify a subgroup of patients with a higher risk of suicide among self‐harming adolescents, we encourage further research to validate our data and possibly introduce laser‐evoked potentials in the diagnostic assessment of these patients.Prof. Giorgio Cruccu declares to have a consulting contract with Angelini and Byogen and a research grant and personal fees with Alfasigma. Prof. Andrea Truini declares to have a relationship with Alfasigma, Angelini, Pfizer and Grunenthal as speaking fees. The other authors have nothing to declare.CL, SG and AT designed the experiment; CL, SG, AT, SM, VM, LB, CP and MF collected the data; CL and CM analysed the data; CL, SG, AT, GC, MF drafted the manuscript and gave final approval.Table S1Click here for additional data file.Table S2Click here for additional data file.Supplementary MaterialClick here for additional data file.


Background: The unique properties of methadone make it attractive for use in cancer pain. The use of very low initial doses of adjunctive methadone is a promising strategy given its simplicity and potentially reduced risk profile.Objective: To understand if an ultralow-dose (ULD) methadone protocol  can improve pain control in outpatients with cancer-related pain not responsive to previous opioids and/or nonopioid analgesics. We also sought to assess if the use of ULD methadone resulted in improvement in mood and sleep among other outcomes.Design and Setting/Subjects: This study is a retrospective chart review of outpatients at the cancer pain clinic at the Tom Baker Cancer Centre in Calgary, Alberta, Canada.Measurements: The mean ratings in maximum and average pain before methadone initiation, and at the final follow-up point are reported. Paired sample t tests evaluate for statistically significant differences in pain ratings before methadone initiation and at final follow-up. We also report the proportion of participants with a subjective improvement in pain, sleep, and mood (dichotomous “yes/no”), and the mean number of weeks to initial documented pain improvement.Results: 68.6% of patients (24/34) reported a subjective improvement in pain. Most patients reported improved sleep and mood .Conclusions: More than two-thirds of patients reported an improvement in pain with a protocol using very low initial doses of adjunctive methadone. Our report is a preliminary retrospective chart review and larger prospective trials are warranted. R-methadone has mu and delta agonist opioid properties, whereas S-methadone is an N-methyl-d-aspartate (NMDA) antagonist and a serotonin and norepinephrine reuptake inhibitor as nonopioid properties. The racemic mixture has a long and highly variable half-life of 7–150 hours.2 The unique properties of methadone, namely NMDA antagonism and serotonergic and norepinephrine activity, make it a promising drug for use in cancer pain.2–5Methadone is a synthetic opioid that was first produced in the 1930s6–9 Although these methods are used in inpatient palliative care settings, they may be associated with unstable pain control in the transition period, sedation, and narcosis, and usually require inpatient monitoring.10 The use of very low initial doses of adjunctive methadone is a promising strategy given its simplicity, potentially reduced risk profile and the addition of a drug with unique properties that are not offered by other opioids.Present evidence-supported methods for use of methadone involve complete rotations off previous opioids and onto relatively high doses of methadone as the sole opioid.11 Our study looks at a relatively unique protocol that starts at “ultralow doses” (ULDs) of 1 mg once daily with a slowly titrated regimen thereafter. The objective is to understand if the use of a ULD methadone protocol can improve pain control in outpatients with cancer-related pain not responsive to previous opioid and/or nonopioid analgesic treatments. We also sought to assess if the use of ULD methadone resulted in improvement in mood and sleep and allowed for a reduction in the primary opioid or other adjuvant analgesics.A 2019 systematic review found only seven studies on the use of low-dose methadone, with variable dosing strategies.This study is a retrospective chart review of outpatients at the cancer pain clinic at the Tom Baker Cancer Centre in Calgary, Alberta, Canada. The study period was from January 2013 to May 2019.Adults aged ≥18 years seen at the Tom Baker Cancer Centre Pain Clinic with pain caused by cancer or cancer treatments and who received ULD methadone and slow titration treatment were included in this study. This clinic sees patients with active cancer as well as those who have previously been treated for cancer and are in remission but continue to have ongoing chronic pain . ULD methadone treatment involves starting at a dose of 1 mg by mouth before bedtime and is titrated weekly for the first four to five weeks and then as needed , cancer type and stage, and cancer treatments received during methadone intervention period. Other data extracted include the type of opioids used and dose, converted to morphine-equivalent daily dose (MEDD), adjuvant analgesics used and dose, and the presence, type, and severity of any reported analgesic-related adverse effects. The conversion from other opioids to MEDD utilized the following rations: 2:1 for oxycodone to morphine; and 5:1 for hydromorphone to morphine. The drug conversion ratios for fentanyl to morphine corresponded to the dose conversion tables found in fentanyl transdermal drug monograph documents  and the mid-point of each range was utilized . These variables were collected both at baseline (before methadone initiation) and at the final follow-up time.We also collected the final documented dose of methadone, pain rating at baseline and at the final follow-up point on a scale from 0 to 10 , the time to initial documentation of pain improvement on methadone, and patient reports of improvement in sleep or mood at the last follow-up point (dichotomous “yes/no” variable). More specifically, in person or phone follow-ups initially occurred weekly for the first four to five weeks and then every two to three weeks or sooner if issues arose such as poorly controlled pain or adverse effects. Patients were able to call the clinic office if questions or issues arose. The clinical practice is to ask if mood “has improved” at each follow-up time. Clinic team members also ask if sleep has improved (“yes or no”) at each of these follow-up times. Finally, at each follow-up patients are asked to rate their “worst pain” for that day and their “average” pain that day from 1 to 10, with 10 being the worst pain they have ever experienced.t tests evaluate for statistically significant differences in pain ratings before methadone initiation and at final follow-up. The mean MEDD of the primary (nonmethadone) opioid at baseline and at the time of final follow-up are presented along with Wilcoxon signed-rank test to assess for statistically significant differences in MEDD at baseline versus final follow-up. The proportion of participants on nonopioid analgesics at baseline and at final follow-up point was also calculated. We also report the proportion of participants with a subjective improvement in pain, sleep, and mood (dichotomous “yes/no”), and the mean number of weeks to initial documented pain improvement.Descriptive summaries are presented for baseline demographic variables. The mean ratings in maximum and average pain before methadone initiation, and at the final follow-up point are reported. Paired sample A total of 35 patients are included in this study with a mean age of 61 years. Twenty-one patients (61%) were female and 17 (48.6%) received cancer treatment during the study period. 74.3% of patients had advanced cancer (stage III–IV), with the most common cancer types being gastrointestinal (22.9%); gynecological (20.0%); and multiple myeloma (17.1%). More than half (54.3%) of patients had mixed pain types, and 45.7% had neuropathic pain as the sole type of pain.68.6% of patients (24/34) reported a subjective improvement in pain, with a mean of 5.4 weeks to initial pain improvement. At baseline, three patients (9%) were not using another strong opioid. At the final follow-up point, this increased to 15 patients (42.9%). Mean follow-up duration was 55.6 weeks. The final follow-up time was defined by one of the following: (1) the last time the patient was seen in clinic before death or discharge from the clinic; (2) the last clinical follow-up within the study timeline.t testing reaching statistical significance . Patients' rating of “average pain” before and after methadone treatment showed a mean difference of −1.4 (SD 2.1) with a statistically significant paired t test value . Most patients reported improved sleep and mood  and 22.9% reported at least one adverse effect (Ten patients (28.6%) discontinued methadone at a mean of 19.2 weeks with reasons, including sedation, patient preference, dizziness, nausea, concerns regarding opioid diversion, intolerance, and unspecified. There were no methadone-related hospitalizations or deaths. The mean difference in maximum pain rating before versus at the final follow-up time was −2.6 (standard deviation [SD] 2.15), with paired sample e effect .Z = −4.7; p < 0.001). The median total daily adjuvant methadone dose at the point of final follow-up was 9 mg (IQR 3–23). The proportion of patients on co-analgesics was slightly reduced for most medications at the final follow-up time compared with baseline (The median primary (nonmethadone) opioid dose, expressed as MEDD, at baseline was 65 mg (interquartile range [IQR] 40–120) and at the final follow-up point was 20 (IQR 0–34). Wilcoxon signed-rank tests showed a statistically significant difference between these two time points . In addition, opioid equianalgesic doses are not easy to calculate as previous studies have suggested wide variability in equianalgesic dosing.