The primary outcome is the difference in numeric rating scale pain scores between grouped interventions, using affective descriptors within the Short-form McGill Pain Questionnaire-2. Secondary outcomes include pain self-efficacy, concomitant analgesic medication-use and adverse events. Additionally, fMRI will be employed to assess brain connectivity related to neuroanatomic pain circuits at baseline, placebo and Transvamix® interventions. The study was approved by the ethical committee at the University Medical Center of Groningen in the Netherlands. Results will be submitted for publication in a peer-reviewed journal.Patients with the genetic blistering skin condition epidermolysis bullosa (EB) report severe pain as a consequence of skin and mucous membrane lesions including blisters, wounds, and scars. Adequate symptom alleviation is not often achieved using conventional pharmacologic interventions. Finding novel approaches to pain care in EB is imperative to improve the quality of life of patients living with EB. There are several anecdotal reports on the use of cannabinoid-based medicines (CBMs) by EB patients to reduce the burden of symptoms. However, controlled clinical investigations assessing these reported effects are lacking. As the pain quality “unpleasantness” delineates EB pain, we hypothesize the modulation of affective pain processing in the brain by way of intervention with CBMs comprising the cannabinoids Δ-9-tetrahydrocannabinol and cannabidiol—objectified by functional magnetic resonance imaging (fMRI). The C4EB study is an investigator-initiated, single-centre, randomized, double-blind, placebo-controlled and crossover trial. Adult patients with the diagnosis epidermolysis bullosa, reporting chronic pain will be eligible to participate. Following baseline measurements, participants will be randomized to receive the sublingually administered interventions placebo and TransvamixTrial registration number: Netherlands Trial Register: NL9347 (Acronym: C4EB). Patients with the genetic blistering skin condition, epidermolysis bullosa (EB), report a significant impact on quality of life compared to other skin conditions . EB is cEndogenously produced cannabinoids (endocannabinoids) play a key role in the modulation of pain signals by binding endocannabinoid receptors 1 and 2 (CB1/2) , 12. CB1It is important to note that the use of cannabinoid-based medicines (CBM) for pain, often as self-medication, have preceded clinical studies and sufficient clinical evidence. Given the limited effectiveness of conventional treatments in EB, it is well-known that these patients have used CBMs for symptom alleviation and have subsequently reported promising anecdotes. A recent study collected data on 71 EB patients around the world using CBMs. Although the cohort mainly comprised patients with a more severe EB, all EB-types described symptomatic improvements. A considerable obstacle to interpreting these experiences is the significant variability in administration forms, cannabinoid compositions, and doses used by patients. Additionally, these products are often not regulated as pharmaceutical products and therefore lack pharmaceutical-grade standardisation and quality control. However, seventeen of the participants administered CBMs sublingually and retrospectively reported mean NRS (0–10) pain reductions of 3.58 (±1.8) after administering CBMs .In the Netherlands, CBMs are produced and compounded by companies overseen by the Dutch government and have been available on prescription since 2003. From 2015 CBM oils comprising THC and CBD in varying ratios have been empirically prescribed to several Dutch patients with EB . Good quTo date, it has also been shown that neither the dose administered nor detected plasma levels of cannabinoids are good predictors of pain alleviation when treated with CBMs. The high inter-individual variability (CV%) is likely due to patient variations in BMI, enterohepatic circulation, degradation in the gut, previous cannabinoid exposure, the endogenous cannabinoid system (endocannabinoid system) compositions and differences in administration technique , 27.Therefore, the current best-practice is for patients administering CBMs to undergo dose-escalation titration following a premeditated dosage build-up scheme . In order to achieve an effective dose, patients continue titration until side-effects are reached, then reduce their dose by one step in the titration scheme, and subsequently maintain the achieved dose . Methods®, a sublingually administered and standardized CBM, on pain, brain connectivity, doses achieved through titration and adverse events. New fMRI techniques to assess brain connectivity enhance the assessment of both baseline connectivity characteristics in EB patients with pain, as well as connectivity changes in areas processing pain affect. In the clinical research setting it is therefore imperative to standardize dose-escalation schemes, administer standardized pharmaceutical grade CBMs, apply validated patient reported outcomes, and employ sufficient sample sizes and rigorous statistical analyses. We hypothesize a novel avenue of pain intervention for EB by modulating pain affect–objectified by fMRI.Taken together, the unmet treatment needs for pain in EB and moderate quality evidence for the use of CBMs to treat pain and modulate pain affect, open grounds for further clinical investigation. To substantiate this research avenue, CBM interventions in EB, the proposed explorative study will gain insight into effects of Transvamix® (100mg/mL THC / 50mg/mL CBD) to treat chronic pain in Epidermolysis Bullosa. This is an explorative study because cannabinoid-based medicines (CBMs), Transvamix-like drugs, have not yet been studied by way of controlled trials in the EB patient population. The addition of placebo mitigates confounding participation bias. The crossover design reduces the number of participants required, an important factor when studying rare diseases, and supported by randomization and blinding, enables rigorous statistical analyses. In addition to this, effects of group outcomes on a group level can be analysed. Participant inclusion will commence in Q4 of 2022 for a period of 6 months. Study completion is expected in Q4 of 2023. After completion, analysis will be performed whereby results publication is expected in Q4 of 2023.The study design is an explorative, randomized placebo-controlled and double-blind intervention crossover study: TransvamixParticipants in this study are adult patients with a confirmed diagnosis  of inherited epidermolysis bullosa (EB). All patients with EB in the Netherlands are registered at the Dutch Expertise Centre for Blistering Diseases, Department of Dermatology, University Medical Centre Groningen. To participate, patients must be currently living in the Netherlands and are at least 16 years of age. Participation is not limited to one sex, nor to any ethnic group. Written informed consent will be obtained and stored in a locked cabinet at the research centre.® or placebo will be delivered by courier to participants 3 days before the allocated commencement of treatment administration. Instructions for administration are provided both verbally and in writing to participants.Eligible participants, who have consented to participation, will undergo inclusion screening at the research centre. Subjects must meet all the following criteria . The Tri®, a cannabinoid-based medicine (CBM) comprising 100mg/mL THC (delta-9-tetrahydrocannabinol) and 50mg/mL CBD (cannabidiol) . Transvamix® is prepared by Felix Farma B.V. using pharmaceutical-grade cannabis produced by Bedrocan B.V., and isolated using an ethanol-based extraction process. The product, Transvamix®, has a standardized cannabinoid composition within regulatory margins. The placebo formulation is comparable in texture, colour, and taste. Identical packaging and labelling will be used. Both Transvamix® and placebo will be administered using a 1 ml dosing syringe.The investigational medicinal product (IMP) is Transvamix®) and placebo in forward (T→P) or reverse (P→T) orders, depending on treatment arm allocation after randomization (® and placebo) will be provided by Felix Farma B.V. A washout of two weeks between both interventions, based on cannabinoid metabolite half-lives, will mitigate carry-over effects.Participants will receive both the IMP (Transvamixmization . The stuAll participants will follow the predetermined titration scheme . The tit® and placebo). Both placebo and IMP (Transvamix®) will undergo the same titration scheme. The maximum dose is 0.75ml/day Transvamix® or placebo (divided between 4 separate administrations). See This achieved dose will be maintained for the remaining intervention period until day 14 is completed for each intervention  will be compiled, consisting of four independent members with expertise in: clinical pharmacology, longitudinal research statistics, EB clinical care, and pain/cannabinoid research. The DSMB will maintain an overview of (serious) adverse events and offer independent advice for premature completion or termination of the study.Participants will continue treatments, including analgesic regimens, according to their current prescriptions and EB breakthrough pain guidelines –which inStudy data will be collected and managed using REDCap electronic data capture tools hosted at the research centre , 32. REDSubjects can leave the study at any time for any reason if they wish to do so without any consequences. The investigator can decide to withdraw a subject from the study for urgent medical reasons or non-compliance.® vs. placebo).The primary outcome is the change score for numeric rating scale (NRS) values using the affective descriptors from the short-form McGill Pain Questionnaire 2 (SF-MPQ2). This will be measured as the grouped difference in mean NRS scores pre- (baseline) and post- intervention (Transvamix® vs. placebo) scores. The instruments used are the SF-MPQ2 and Pain Self Efficacy Questionnaire (PSEQ) comprising NRS values. Additionally, change scores for global pain and pruritus will be measured using visual analogue scales (VAS 0–100).The secondary outcomes will include data derived from other patient reported outcome measurements (PROM). These outcomes will be measured as grouped differences, change scores, in mean pre- (baseline) and post-intervention  of side-effects will be reported and compared between Transvamix® and placebo.Functional MRI data pertaining to brain connectivity will be analysed between placebo and TransvamixLastly, analgesic medication changes, of currently used medications reported at baseline, will be reported by participants at the end of each intervention. Reductions in- or increased use will be quantified and compared between intervention groups.https://bscs.umcg.nl/nl/faciliteiten/cognitive-neuroscience-center/), using a multi-echo echo-planar T2*-weighted imaging sequence with 550 volumes (voxel size of 2.5 × 2.5 × 2.5 mm3 [3). An experienced MRI technologist will examine all structural images to ensure the absence of structural abnormalities in the brain. In case of an abnormality, the participant will be referred to their general practitioner for further examination or referral.Whole-brain fMRI blood oxygen-level dependent data will be acquired on a 3T Siemens Magnetom Prisma with a 64-channel head coil at the Cognitive Neuroscience Centre in Groningen  from a recent study in Dutch patients with EB who had pain scores >3. In 28 patients, mean NRS pain scores were 5.76 ± 1.45 .To establish a significant reduction in pain scores of 30%, with a power of 80% and a 0.05, the minimum sample size is 9 (or 5 participants in each study arm)To establish a significant reduction in pain scores of 50%, the minimum sample size is 5 (or 3 participants in each study arm).Owing to the rarity of EB and the strict inclusion criteria for age and chronic pain, the estimated feasible participant recruitment number is 16. For this study we aim to include 16 participants (8 in each study arm).All data will be recorded in the eCRF REDCap, completed by either the researcher or participant, when prompted. Data will be handled confidentially and accordingly to the European guidelines for privacy protection (AVG). Research participants will be pseudonymized, personally traceable data removed, and will be identified using a participation number. Data will be stored for a minimum of 15 years after study closure.®). The change scores for baseline to placebo and Transvamix® will be computed and incorporated for statistical testing. Visual inspection of data and a Shapiro Wilk test will be used to check for normality. Next either t-testing (paired and independent samples t-testing) or non-parametric tests (including Wilcoxon signed rank test) will be used depending on the distribution observed. The significance level will be set to p<0.05. In addition, mixed effects models will be applied, allowing for analysis of longitudinal data, missing data, and possible period effects.Primary and secondary outcomes will be presented using descriptive statistics , and subdivided into three groups  [https://web.conn-toolbox.org; RRID:SCR_009550) [® we will primarily perform a seed-based correlation analysis, to determine the functional connectivity between the seed regions, the anterior cingulate cortex (ACC) and amygdala, and other areas in the brain. Changes in brain connectivity (baseline vs. Transvamix® vs. placebo) will be explored in individual participants and on the group level. The neural effects of the intervention will be correlated against primary and secondary outcome measures.The resting-state multi-echo fMRI dataset will be preprocessed using the ME-ICA pipeline (latest/) , 35. ME-_009550) . To studCentrale Commissie Mensgebonden Onderzoek, CCMO, the National Medical Ethical Committee in the Netherlands). The EudraCT number is 2021-000103-20. The trial was registered prospectively in the Netherlands Trial Register (NL9347). Changes to the study protocol will be submitted to the CCMO in amendments for approval.The methods employed in this trial were judged and approved by the Central Committee on Research Involving Human Subjects (This is a study supported by the patient organization Dystrophic Epidermolysis Research Association United Kingdom (DEBRA-UK).In summary this explorative study will assess the use of pharmaceutical grade CBMs comprising THC and CBD in patients with EB suffering from chronic pain. The controlled cross over design of the study minimizes the burden of participation and maximizes the methodological reproducibility by employing standardized interventions and objective research outcomes. Both the chosen methodology and eventual results highlight a novel research avenue and will cornerstone future clinical research in EB and CBMs.S1 Checklist(DOC)Click here for additional data file.S1 Protocol(PDF)Click here for additional data file.


Recent studies exhibited the unstable prediction ability of blood-based tumor mutational burden (bTMB) when predicting the response of immune checkpoint inhibitors (ICIs) therapy in patients with non-small cell lung cancer (NSCLC). Circulating tumor DNA (ctDNA) abundance, usually represented by maximum somatic allele frequency (MSAF), was one possible confounding factor influencing bTMB ability in ICIs response prediction. We herein developed a novel approach to optimize the calculation of bTMB by integrating MSAF, namely, MSAF-adjusted bTMB (Ma-bTMB), to better select beneficiaries of ICIs. Our present results showed that this novel non-invasive biomarker could reduce the confounding effect of MSAF and ITH on bTMB calculation and effectively identify beneficiaries of ICIs in patients with advanced NSCLC, warranting future clinical trials.n = 1679), Zhuo (n = 35), Wang (n = 45), POPLAR  and OAK  cohorts. Results: MSAF demonstrated a modest positive correlation with bTMB and a negative one with survival benefit. Improved survival outcomes of ICIs therapy have been observed among patients with high-Ma-bTMB compared to those with low-Ma-bTMB in Zhuo and Wang cohorts. In addition, compared to low-Ma-bTMB, high-Ma-bTMB was associated with more positive clinical benefits from ICIs therapy than chemotherapy both in POPLAR and OAK cohorts. Further exploration suggested that Ma-bTMB could precisely identify more potential ICIs beneficiaries compared to bTMB and LAF-bTMB, complementary to PD-L1 expression. Conclusions: We developed Ma-bTMB, a convenient, readily available, non-invasive predictive biomarker effectively differentiates beneficiaries of ICIs therapy in advanced NSCLC, warranting future clinical trials.Introduction: Recent studies exhibited the unstable prediction ability of blood-based tumor mutational burden (bTMB) when predicting the response of immune checkpoint inhibitors (ICIs) therapy in patients with non-small cell lung cancer (NSCLC). Circulating tumor DNA (ctDNA) abundance, usually represented by maximum somatic allele frequency (MSAF), was one possible confounding factor influencing bTMB ability in ICIs response prediction. Methods: MSAF-adjusted bTMB (Ma-bTMB) was established and validated in patients with advanced NSCLC among Geneplus Cancer Genome Database (GCGD,  Immune checkpoint inhibitors (ICIs), targeting programmed death-ligand 1 (PD-L1) or programmed death 1 (PD-1), have been found to be associated with improved overall survival (OS) of patients with advanced non-small cell lung cancer (NSCLC) ,3. HowevThough PD-L1 expression and tissue-based tumor mutational burden (tTMB) have been proven to be useful predictive biomarkers for patients with advanced NSCLC treated with ICIs ,5, suffiDifferent from tTMB obtained through local tumor biopsy, bTMB is calculated based on circulating tumor DNA (ctDNA) derived from all tumor niches, implying intratumor heterogeneity (ITH) and tumor burden in a patient with advanced cancer ,12. ctDNWith the development of targeted genomic sequencing assays, a simple, steady, and propagable modified bTMB algorithm that could identify both OS and PFS beneficiaries from ICIs treatment across various panels and calling principles is needed. In this study, we identified MSAF as the core confounding factor of bTMB in survival prediction of ICIs therapy, according to which we established and validated a novel predictive biomarker MSAF-adjusted bTMB (Ma-bTMB) in patients with advanced NSCLC among Zhuo, Wang, POPLAR, and OAK cohorts. Finally, the application of Ma-bTMB was compared with that of other bTMB biomarkers and PD-L1 expression.n = 35) and Cancer Hospital of Chinese Academy of Medical Sciences & Peking Union Medical College  from 25 August 2016 to 12 April 2019. Patients with MSAF = 0 were excluded due to incalculableness . All patients were pathologically diagnosed and underwent anti-PD-(L)-1 therapy. The baseline characteristics, mutational information, and clinical information of Wang and Zhuo cohorts are presented in Eighty patients with stage III–IV NSCLC were enrolled from two centers, Peking University Cancer Hospital & Institute , which is an internal database of Geneplus Co., Ltd. . To verify that Ma-bTMB is associated with ICIs rather than chemotherapy response, POPLAR (NCT01903993) and OAK (NCT02008227) cohorts, two large randomized clinical trials investigating the efficacy and safety of atezolizumab  compared with docetaxel (chemotherapy) in patients with NSCLC, were obtained from a published study and included in the subsequent algorithm analysis [n = 642). Among these patients, 106 received docetaxel therapy and 105 received atezolizumab therapy in the POPLAR cohort, with 318 vs. 324, respectively, in the OAK cohort [To analyze the association between MSAF and bTMB, somatic single nucleotide variations (SNVs) and indels detected in the ctDNA by 1021-gene-panel from the plasma of 1679 Chinese NSCLC patients enrolled from 1 July 2018 to 12 March 2020, were downloaded from Geneplus Cancer Genome Database (GCGD) cohort . Next, circulating free DNA (cfDNA) was extracted using a DNeasy Blood Kit  and QIAamp Circulating Nucleic Acid Kit (Qiagen). White blood cells from the same patient were used as control. Sequencing libraries were constructed utilizing the KAPA DNA Library Preparation Kit  per the manufacturer’s instructions. Barcoded libraries were subsequently hybridized to a customized panel of 1021 genes, consisting of whole exons and selected introns of 288 genes, along with selected regions of 733 genes. A detailed gene list was described in our previous study [Blood samples were collected in EDTA vacutainer tubes  and subjected to ctDNA extraction and sequencing within 3 hours. Peripheral blood lymphocytes and plasma were separated via sequential centrifugation 1 treatment until either objective disease progression (assessed by an investigator using RECIST version 1.1) or death from any cause. OS was defined as the time from the start of anti-PD-(L)1 treatment until death from any cause. We censored patients who had not progressed, who had died at the time of statistical analysis, or who failed to follow up but had not died at the time of their last evaluation.p-value was obtained from an unstratified proportional Cox model, including the terms of treatment, the biomarker subgroup, and treatment by the biomarker subgroup interaction. For all analyses, p < 0.05 was considered statistically significant. IBM SPSS software (version 24.0), GraphPad Prism (version 9.0), and R 4.2.0 were used for the statistical analysis.Pearson correlation tests were employed to determine the association between MSAF and OS/PFS or bTMB. Kaplan–Meier curves were plotted and, together with log-rank tests, performed to calculate the hazard ratios (HRs) and evaluate the prognostic value of various markers. The interaction n = 31) and Wang  cohorts and 851 patients with advanced NSCLC receiving anti-PD-(L)-1 or chemotherapy from POPLAR  and OAK  cohorts. PD-L1 expression was only available in the OAK cohort (n = 635).The study design is illustrated in p < 0.001) and PFS  as well as between MSAF and subclones  in GCGD cohort , there was a higher level of subclonal mutations in the high-bTMB group than in the low-bTMB group  in Wang and Zhuo cohorts  or subclonal mutation level , suggesting that Ma-bTMB could adjust bTMB by balancing the effect of ITH on stratification.To explore whether Ma-bTMB balances the poor prognosis effect of ITH, we compared subclones and subclonal mutations between high and low groups divided by bTMB and Ma-bTMB. A 25% increase in the bTMB value with a cutoff score of 14 was defined as the cutoff point; the Ma-bTMB cutoff score of 10 was selected as the HR and  cutoffs B. Even tp < 0.001) and OS  in patients with anti-PD-(L)1 therapy than low-Ma-bTMB  and OS  compared with low-Ma-bTMB 1 therapy in Zhuo cohort, and found that high-Ma-bTMB (≥10) was significantly related with prolonged PFS  and OS (p = 0.022), as shown in p = 0.010, p < 0.001, p = 0.636; OS: 9.6 vs. 9.2 months, HR = 0.79, 95% CI 0.62–1.00, p = 0.051). The interaction p-values between Ma-bTMB and different treatment (atezolizumab vs. docetaxel) were significant in both PFS  and OS (Interaction p = 0.013). Taken together, these results supported the notion that Ma-bTMB was proficient in identifying patients who may receive more benefit from ICIs therapy rather than chemotherapy.In the POPLAR cohort, the Ma-bTMB cutoff score of 17 was selected, with HR and  cutoffs . In patip = 0.011, p = 0.119, p < 0.001, p-value for OS between Ma-bTMB and treatments was significant in PD-L1 negative expression group . For PD-L1 negative expression group, there was similar trending for PFS benefit in patients receiving atezolizumab though without significant difference  and PFS  benefit from ICIs, as shown in p = 0.126). However, bTMB could not predict OS (p = 0.974) nor PFS (p = 0.198) in the Wang & Zhuo cohort. In the OAK & POPLAR cohort, patients receiving atezolizumab were associated with significantly longer OS and PFS than patients receiving docetaxel among high-Ma-bTMB, high-bTMB, high-LAF-bTMB groups while the significant interaction p-values were only observed in Ma-bTMB  and LAF-bTMB  biomarkers -bTMB as a predictive biomarker in patients with advanced NSCLC receiving anti-PD-(L)1 . We thenomarkers B,C. ThouIn this study, we discovered that high-Ma-bTMB could predict the PFS and OS benefit of anti-PD-(L)1 therapy while serving as an effective predictive biomarker for selecting patients who could benefit from atezolizumab rather than chemotherapy. Patients with high-Ma-bTMB showed approximately 11 months longer OS in Zhuo (17.6 vs. 6.6 months) and Wang (14.4 vs. 3.6 months) cohorts after receiving ICIs, as well as about 8 months improved OS in POPLAR (15.6 vs. 7.8 months) and OAK (16.2 vs. 8.3 months) cohorts after receiving ICIs compared to chemotherapy. Even in patients with PD-L1 negative expression, those with high-Ma-bTMB receiving atezolizumab still had longer OS than chemotherapy. Our study showed that Ma-bTMB could steadily select ICIs beneficial populations in advanced NSCLC.The establishment of Ma-bTMB is needed. With the revelation of subsequent clinical trials with long follow-ups, such as Keynote-001 and CheckMate-067, etc., it becomes clearer that ICIs therapy provides long-term benefits over conventional treatments, and identifying OS benefit is of great importance ,17,18. AThe establishment of Ma-bTMB is reasonable. Distinct from tTMB, the analysis of bTMB had been found to be impacted by several factors in the blood, including ctDNA, AF, MSAF grouping, ITH, etc. ,22,23,24Genetically distinct cellular populations, resulting from clonal expansions, spatial segregation, and incomplete selective sweeps, were manifested as ITH . MoreoveP for OS between Ma-bTMB and treatment subgroups was significant in patients with PD-L1 negative expression and not significant in patients with PD-L1 positive expression. Patients with PD-L1 positive expression and high-Ma-bTMB showed the longest OS benefit (17.3 months) among all, and those with high-Ma-bTMB had 9 months longer OS after ICI therapy over chemotherapy (15.9 vs. 6.3 months) in patients with PD-L1 negative expression. Intriguingly, regardless of PD-L1 expression, patients with low-Ma-bTMB receiving ICIs therapy showed neither PFS nor OS benefit compared to chemotherapy. In this scenario, a combination biomarker of PD-L1 expression and Ma-bTMB analysis could guide the treatment selection between ICIs and chemotherapy.Although PD-L1 expression, tested via immunohistochemistry assays, is currently considered the most widely accepted biomarker guiding the selection of patients to receive anti-PD-L1/PD-1 treatment , patientPreviously, we developed an adjusted bTMB algorithm, LAF-bTMB, by removing high AF mutations to predict the clinical benefit of PD-(L)1 inhibitors in patients with advanced NSCLC . In thisThere are several limitations to this study. First, the algorithm was developed retrospectively, and the sample size of the Wang and Zhuo cohorts was relatively small, which could bias the results. In addition, the detection platforms and methodologies differed in POPLAR&OAK and Wang & Zhuo cohorts. A larger prospective study is warranted for further validation. Nevertheless, the stable prediction ability of Ma-bTMB between these two platforms (1021-gene-panel and F1CDx NGS assay) and four cohorts  indicated its feasibility, to some extent, as a predictive biomarker of ICI benefit in patients with advanced NSCLC.In summary, although a larger prospective study is necessary for further verification, we developed and validated a convenient and readily available novel algorithm, Ma-bTMB, that can predict clinical benefits to guide ICI therapy in patients with advanced NSCLC.


This pilot randomized clinical trial (RCT) assessed the feasibility of a full-scale RCT to compare the outcomes of opioid analgesia vs opioid-free analgesia prescribed to adult patients after undergoing outpatient general surgery. Is it feasible to conduct a randomized clinical trial (RCT) comparing opioid analgesia with opioid-free analgesia after outpatient general surgery?In this pilot RCT, 76 patients were randomized 1:1 to receive opioid or opioid-free analgesia after postoperative discharge. The trial proposed was well accepted by the stakeholders involved, including patients and clinicians, and all a priori feasibility criteria were fulfilled.These findings support the feasibility of an RCT to prospectively compare opioid analgesia with opioid-free analgesia after hospital discharge following outpatient general surgery. The overprescription of opioids to surgical patients is recognized as an important factor contributing to the opioid crisis. However, the value of prescribing opioid analgesia (OA) vs opioid-free analgesia (OFA) after postoperative discharge remains uncertain.To investigate the feasibility of conducting a full-scale randomized clinical trial (RCT) to assess the comparative effectiveness of OA vs OFA after outpatient general surgery.This parallel, 2-group, assessor-blind, pragmatic pilot RCT was conducted from January 29 to September 3, 2020 . at 2 university-affiliated hospitals in Montreal, Quebec, Canada. Participants were adult patients (aged ≥18 years) undergoing outpatient abdominal  or breast  general surgical procedures. Exclusion criteria were contraindications to drugs used in the trial, preoperative opioid use, conditions that could affect assessment of outcomes, and intraoperative or early complications requiring hospitalization.Patients were randomized 1:1 to receive OA (around-the-clock nonopioids and opioids for breakthrough pain) or OFA (around-the-clock nonopioids with increasing doses and/or addition of nonopioid medications for breakthrough pain) after postoperative discharge.Main outcomes were a priori RCT feasibility criteria . Secondary outcomes included pain intensity and interference, analgesic intake, 30-day unplanned health care use, and adverse events. Between-group comparison of outcomes followed the intention-to-treat principle.A total of 15 surgeons were approached; all  agreed to have patients recruited and adhered to the study procedures. Rates of patient eligibility and consent were 73%  and 57% , respectively. Seventy-six patients were randomized (39 [51%] to OA and 37 [49%] to OFA) and included in the intention-to-treat analysis ; 40 (53%) underwent abdominal surgery, and 36 (47%) underwent breast surgery. Seventy-five patients  adhered to the allocated treatment; 1 patient randomly assigned to OFA received an opioid prescription. Seventeen patients (44%) randomly assigned to OA consumed opioids after discharge. Seventy-three patients  completed the 30-day follow-up. The rate of missing questionnaires was 37 of 3724 . All the a priori RCT feasibility criteria were fulfilled.The findings of this pilot RCT support the feasibility of conducting a robust, full-scale RCT to inform evidence-based prescribing of analgesia after outpatient general surgery.NCT04254679ClinicalTrials.gov Identifier:  Findings from a scoping review suggest that the number of randomized clinical trials (RCTs) in the field of pain management is limited,11 although existing small trials often challenged the value of prescribing opioids for postdischarge analgesia after general surgery.14 Owing to a lack of evidence in this research area, the decision to prescribe opioids largely depends on surgeons’ preference and the health care culture; hence, there is an urgent need for robust RCTs to guide clinical decision-making.The overprescription of opioids by surgeons is recognized as a contributing factor to the current crisis of opioid misuse and addiction in North America.15 Undertaking an RCT with OFA raises important practical concerns including surgeon and patient hesitation about pain treatment without opioids, the randomization approach, adherence, and optimal outcome measurement. Thus, the objective of this pilot study was to investigate the feasibility of conducting a full-scale RCT to assess the comparative effectiveness of analgesia regimens including opioids (OA) vs OFA regimens after outpatient general surgery.Owing to the complexity inherent in well-designed RCTs, pilot studies are a critical first step to assess acceptability, test logistical needs, optimize design, and inform the capacities required for a full-scale trial.NCT04254679). Analyses and reporting followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline extension for pilot trials . Patients were excluded postoperatively if they had intraoperative or early complications requiring a hospital stay.This was a parallel, 2-group, assessor-blind, pragmatic pilot RCT with participants allocated 1:1 to receive OA or OFA after postoperative discharge. Recruitment of participants occurred between January 29 and September 3, 2020 . The trial was halted from March 15 to June 1, 2020, owing to COVID-19 restrictions. We included adult patients (aged ≥18 years) undergoing outpatient abdominal  and breast  general surgical procedures at 2 university-affiliated hospitals in Montreal, Quebec, Canada. All surgeries were performed by fellowship-trained surgeons; the surgeons’ agreement to have patients in the trial was required for inclusion. We excluded patients with contraindications to the drugs used in the trial ,20) by an external researcher not involved in the trial and was uploaded to REDCap.21 Permuted blocks of varying sizes  were used, and randomization was stratified by abdominal surgery vs breast surgery. There was no stratification by center because the trial sites were specialized in either procedure type. Randomizations were conducted by research staff present in the operating room using the project’s REDCap randomization module. Treatment allocations were concealed until patients were deemed ready to be discharged from the operating room to the postanesthesia care unit.The random allocation sequence was generated electronically , the prescription was kept in a sealed opaque envelope until patients were deemed ready to leave the hospital. Outcome assessors  were blinded to treatment allocations. Blinding effectiveness was estimated by asking assessors to guess the patient’s group allocation after the last follow-up assessment. Any inadvertent unblinding was reported.22 Examples are described in eFigure 1 in The discharge prescription in the OA group (standard care) included around-the-clock nonopioid analgesics  and a supply of opioids to be used as rescue analgesia for breakthrough pain. Given the pragmatic nature of this trial, the specific OA regimen was determined by the patient’s primary surgeon considering the surgical procedure, comorbidities, and patient preference. The OA strategies used at each trial site were guided by the institution’s pain service team and followed Health Canada standards for safety and efficacy.23 targeting individual variances in analgesia response.24 The regimen prescribed was determined by the patient’s primary surgeon. Suggested OFA strategies, developed with input from the pain service team according to Health Canada standards,22 are described in eFigure 2 in The discharge prescription in the OFA group included only around-the-clock nonopioid analgesics . In case of breakthrough pain, rescue analgesia was provided by (1) increasing doses of nonopioid analgesics, (2) adding nonopioid drugs that were not included in the initial regimen, or (3) switching drugs according to single-dose efficacy evidenceam to 4 pm) or visit the hospital emergency department (after hours and weekends) for assessment and potential pain management optimization.In accordance with standard practice at the trial sites, in case of persistent pain despite the available prescription, patients in the OA group were advised to call the surgeon’s office or clinic during working hours . When this line was called, patients were informed about the availability of the opioid prescription.Surgical techniques and in-hospital anesthesia and analgesia interventions were left to the discretion of the surgeons and anesthesiologists to best reflect routine practice. The use of nonpharmacological pain interventions  were permitted and recorded.26), potential for opioid misuse (Screener and Opioid Assessment for Patients With Pain27), preferred treatment group, and expectations for treatment effectiveness. Details are provided in eTable 1 in Details about patient, surgical, and perioperative care characteristics were obtained from electronic medical records. Preoperatively, we also collected self-reported data on pain catastrophizing  at least 90% of the surgeons who conducted the procedures of interest agreed to have patients randomly assigned to treatment and adhered to the agreement , (2) at least 70% of patients undergoing the procedures of interest were eligible to be randomly assigned, (3) at least 50% of eligible patients agreed to participate in the study and were randomly assigned, (4) at least 80% of the patients who were randomly assigned adhered to their allocated treatment , (5) at least 80% of the randomly assigned patients completed an outcome assessment at 30 days, and (6) among patients who completed outcome assessments, the proportion of missing data  was 10% or less.28 time to stopping pain medication,29 Patient-Reported Outcomes Measurement Information System 29 profile ,30 perioperative Opioid-Related Symptom Distress Scale,31 Prescription Opioid Misuse Index,32 30-day complications,34 30-day unplanned health care use , 30-day drug-related adverse events , and prolonged opioid use (3-month follow-up). Details are given in eTable 2 in Clinical outcomes were assessed secondarily to inform the measurement strategy and sample size requirements for a future full-scale RCT . Our outcome measurement strategy included the Brief Pain Inventory–Short Form (pain intensity and pain interference domains),Patient-reported outcomes were collected preoperatively (baseline), on postoperative days 1 to 7, and at postoperative weeks 2 (day 14), 3 (day 21), and 4 (day 28). Data collection was via electronic questionnaires distributed using REDCap and completed on a smartphone, tablet, or personal computer. Electronic data were transmitted directly to a REDCap database and verified by blinded assessors . Patients also had the option to complete questionnaires by telephone with a blinded assessor. Information regarding 30-day complications and unplanned health care use was obtained via self-report with electronic medical record confirmation. Information regarding opioid dispensing was monitored for 3 months on a provincewide medical database (Dossier Santé Québec). Treatment adherence was monitored (via the REDCap questionnaires or telephone) by unblinded study staff not involved in outcome assessment.36 we aimed to recruit and obtain outcome data from 80 patients (40 per group), allowing for an attrition rate of approximately 15%. This sample size is also consistent with recommendations regarding the minimal number of participants required to identify feasibility issues.37In accordance with previous recommendations that at least 70 measured participants are required to estimate SDs with enough precision for future sample size calculations,16 To inform the generalizability of our results, we compared the characteristics of randomly assigned patients with those of patients who did not consent to randomization. All analyses were performed using Stata, version 16 (StataCorp LLC).Feasibility outcomes were estimated using descriptive statistics with 95% CIs. Between-group comparison of outcomes followed the intention-to-treat principle and focused on descriptive statistics and exploratory effect estimates with 95% CIs. Because this was a feasibility trial, no inferential statistics targeting statistical significance were analyzed.All 15 of the surgeons  who conducted the eligible surgeries during the study period agreed to have patients recruited and adhered to the study procedures. The CONSORT diagram is shown in 38 , 25 patients (64%) filled their opioid prescription, and 17 (44%) reported consuming opioids after discharge. In the OFA group, 8 patients (22%) used the rescue nonopioid analgesia available in their prescription. Only 1 patient (3%) in the OFA group  filled an opioid prescription after calling the study hotline owing to uncontrolled pain.Before randomization, most patients stated a preference for being randomly assigned to the OFA group (37 patients [49%]) or had no preference (28 patients [37%]). Thirty-seven patients (49%) expected that OA would be very effective, and 28 (37%) expected that OFA would be somewhat effective. The OA and OFA regimens prescribed at discharge are described in eTable 5 in 40 Domains for the Assessment of Patient-Reported Outcomes Measurement Information System 29 are reported in eFigure 3 in Data regarding postoperative pain intensity and interference are reported in Rates of adverse events identified using the perioperative Opioid-Related Symptom Distress Scale questionnaire are reported in eTable 6 in Findings from this pilot trial support the feasibility of conducting a full-scale RCT to compare OA with OFA after outpatient general surgery. Overall, the trial proposed was welcomed by all the stakeholders involved , supporting recognition of the uncertainty regarding comparative effectiveness of OA vs OFA after postoperative discharge.8 Of note, patients’ option for not taking opioids (even when randomly assigned to receive a prescription) is inherent to a pragmatic trial aiming to assess the value of opioid prescribing in real-world settings.The most common barrier to participation among eligible patients was a lack of willingness to take part in research while receiving care (42 [60%]); however, a considerable proportion of patients (20 [29%]) did not consent to randomization because of preconceptions about the use of opioids for postoperative analgesia. Although some patients (12 [17%]) were concerned about the efficacy of OFA, others (8 [11%]) did not want to take opioids given the risk of addiction and adverse effects . This fi42 Given this concern, trial participants randomized to the OFA group had a study hotline available to report uncontrolled pain and a backup opioid prescription faxed to their pharmacy. During the study period, only 2 patients used the study hotline to report uncontrolled pain. One patient ultimately filled the backup opioid prescription, whereas the other reported improvement after optimizing the dosage of nonopioid drugs (previously taken incorrectly). None of the episodes of unplanned health care use had uncontrolled pain as the chief complaint. However, of note, the overall rates of unplanned health care use tended to be higher among patients randomly assigned to OA (15% vs 3%). Postoperative complications, which were the main causes of emergency department visits and readmissions, also tended to be higher among patients in the OA group (15% vs 5%). Although these findings may have occurred by chance given the study’s small sample size, they warrant further investigation in a full-scale RCT.The prescription of opioids to surgical patients often results from concerns of inadequate pain control after discharge, which may be associated with increased emergency visits and readmissions.16 Our feasibility findings were obtained in 2 tertiary academic hospitals in Canada and may not be generalizable to other contexts of care. Patient recruitment was interrupted owing to the COVID-19 pandemic; we cannot exclude that widespread social isolation may have affected some aspects of the trial . Randomization of patients in the postanesthesia care unit  would have optimized concealment of allocation, but this was considered impractical by surgeons who often write their prescriptions in the operating room after skin closure. Two patients were excluded from the trial after randomization because they had contraindications to nonsteroidal anti-inflammatory drugs not documented in electronic medical records. This indicates that further screening measures are warranted in a full-scale RCT . An ongoing qualitative study involving perioperative care clinicians and patients who participated in the trial will further elucidate challenges and mitigation strategies in preparation for a future full-scale RCT.This study has limitations. This pilot RCT was not statistically powered to detect differences in outcomes, so any between-group comparison should be interpreted with caution.The overprescription of opioids postoperatively is recognized as a contributing factor to the current opioid crisis. Patients undergoing outpatient general surgery are frequently prescribed opioids after discharge, but the value of this practice remains uncertain. Findings from this pilot trial support the feasibility of conducting a robust, full-scale trial to inform evidence-based analgesia prescribing.


Qualitative assessment revealed that 24 of 29 patients experienced an improvement in pain symptoms, 17 of whom experienced complete remission. The results of the qualitative and quantitative analysis provide indications of the effectiveness of the splint therapy. In addition to quantitative measurements, the ultrasound facebow technique was also able to provide qualitative information.Splint therapy is widely used in the treatment of myofascial pain, but valid studies on the efficacy of this therapy are rare. The purpose of the present study was to investigate which qualifiable and quantifiable effects of splint therapy are detectable. For this purpose, 29 patients  diagnosed with myofascial pain (RDC/TMD) were investigated in this prospective clinical trial (10/6/14An). Patients were treated with Michigan splints applied overnight for three months. Before (T1) and after three months of treatment (T2), patients were registered with an electronic ultrasound device with qualitative and quantitative evaluation of the registrations and a qualitative assessment of pain symptoms using a verbal analog scale. Significant differences were found between maximum mouth opening (MMP) ( Temporomandibular disorders (TMD) are a current and widespread problem in the general population, affecting about 5% to 31% of the population . In addiThis longitudinal prospective clinical trial was approved by the Institutional Ethics Committee of the University Medical Center Göttingen (ethics number 10/6/14An) and executed in accordance with the principles of the Declaration of Helsinki. All patients participated in the trial on a voluntary basis after receiving comprehensive information about the aim and design of the study and signing an informed consent form. This report complies with the STROBE guidelines for observational studies.Twenty-nine patients  with myogenic temporomandibular disorders (TMD) and clinical indication for occlusion splint therapy participated in the trial. Patients were treated by the Department of Prosthodontics at the University Medical Center Göttingen and were recruited between July 2014 and March 2016. Of the 32 patients initially screened, 3 female patients were excluded due to non-appearance for follow-up appointments (drop-out rate n = 3). Inclusion criteria were a minimum age of 18 years and the diagnosis of “myofascial pain” (diagnosis I.a and I.b) according to the RDC/TMD criteria (Research Diagnostic Criteria for Temporomandibular Disorders) . ExclusiTo meet the basic inclusion criteria, a myogenic dysfunction had to be diagnosed according to the RDC/TMD Axis I diagnosis “I.a. Myofascial Pain” or “I.b. Myofascial Pain with limited opening” . The diaAfter a TMD diagnosis for myofascial pain, impressions of upper and lower jaw dentition, centric bite registration, and facial arch registration were performed for subsequent Michigan splint fabrication in a dental laboratory. For centric condylar position registration, deprogramming of the masticatory muscles was performed, i.e., cotton rolls were placed between the dentition in an upright sitting and dorsally supported head position for 30 min. Immediately after removal of the cotton rolls, silicone was applied to the mandibular dentition for bite registration with Registrado X-tra . Subsequently, the individual position of the upper jaw in relation to the facial skull was registered by applying a facebow . This was attached to a system-complementary articulator  by means of a mounting plate . After complete adjustment of the model casts in the articulator, an additional spacing of three millimeters was set starting from the zero position of the articulator pin. The bite spacing was thus accentuated in accordance with the concept for the subsequent fabrication of the Michigan splint according to the conventional procedure of Ramfjord and Ash , in a coThe maximum mandibular mobilities in the frontal, horizontal, and sagittal planes of all 29 patients were recorded with an ultrasound electronic ARCUSdigma II device  both before (T1) and three months after splint therapy (T2). A strict registration protocol was applied, where patients were examined in exactly the same examination environment at both T1 and T2. Patients were registered in the dental chair with strict adherence to a precise and reproducible sitting position, requiring the patients to be positioned with their shoulders and torso fully resting against the backrest and their heads supported dorsally against the headrest. Correct cranial positioning via the Frankfurt horizontal was checked throughout the entire measurement period, aligning the electronic facebow with the room plane. The application of the ARCUSdigma II measuring bow was always carried out according to the same scheme, with special regard to the manufacturer’s instructions. For calibration, the KaVo Transfer System  was used to fix the individual reference points for software-integrated articulator programming. The mandibular transmitter unit was attached to a customized para-occlusal tray consisting of silicone applied to labial surfaces  and a prefabricated system bite fork. In both measurements (T1 and T2), the patients were asked to consecutively perform first the maximum mouth opening, followed by the retrusion, as well as the left and right side laterotrusion under tooth contact. All movements began and ended in the maximal intercuspal position (MIP). The KaVo Integrated Desktop software  delivered a function report  on the measurements  made after registration was completed. The content of this report was also outputted in tabular form via Microsoft Excel 2010  for analysis purposes.For the quantitative evaluation of the collected measured values, statistical analysis was carried out, whereas the qualitative evaluation of the function reports was carried out visually. More harmonious and straightforward or more reproducible and symmetrical mandibular movements were evaluated as qualitative visual improvements. Less straight, limited, and asymmetrical movement patterns in the function report were considered to have no qualitative visual therapy result.After 3 months of Michigan splint therapy, all patients were asked for subjective assessment of the therapy success in addition to the final electronic recording of mandibular mobility (T2). The patients were asked about subjective current pain sensation and how facial and jaw pain had changed after splint therapy. All patients were assessed by means of a verbal analog scale, with the following responses being distinguished: (1) no change from baseline, (2) improvement from baseline, (3) complete remission, and (4) exacerbation from baseline.p ≤ 0.05. Examination of the dependent variables for significant differences between the two dependent samples (same patient(s) at two measurement time points) was performed using the nonparametric Wilcoxon test. For final analysis of possible gender-specific differences (independent samples) regarding the variables examined, the Mann–Whitney U test was applied.Data were transferred from the KaVo Integrated Desktop software  to Microsoft Excel 2010  for processing the raw data and then fed into SPSS Statistics Version 24 software  for statistical analysis. Metrically scaled variables were first tested for normal distribution using Kolmogorov–Smirnov and Shapiro–Wilk tests. Based on a non-given normal distribution, for descriptive statistics, metric variables were presented as median, minimum, and maximum as well as interquartile range (IQR). The significance level of all tests was set at To identify any therapeutic effect of occlusion splint therapy on maximum mandibular mobility, the digitally recorded maximum mouth opening values  for all study patients (n = 29) were compared before (T1) and 3 months after continuous splint therapy (T2). Values with a positive sign indicate an increase in mobility and those with a negative sign indicate a reduction in mobility. An increase in the range of motion during mouth opening was observed for every single test patient. The median increase in the range of motion was 6.15 mm, with minimum and maximum values of 0.2 mm and 17.01 mm, respectively .p < 0.001) was found for the collected dependent samples and distinct indications for a therapy-induced increase in the range of motion could be assumed.A highly statistically significant difference (p = 0.045) regarding the range of motion when considering the right but not the left condyle  could be observed after splint therapy in the function reports (ARCUSdigma II). This harmonization was manifested in a lengthening and leveling of the trajectories of movement and an approximation to the classical movements of Posselt’s envelope of motion in the sagittal and transversal plane . The recFinally, the entire study population was evaluated regarding recognizable harmonization of the movement patterns , wherebyA comprehensive improvement in function was observed for 18 patients , i.e., 6Analyzing the function reports in detail, the five refractory patients showed a smaller increase in maximum mouth opening. With a median pre-therapeutic mouth opening of 49.6 mm ± 14.6 mm, a movement increase of 2.6 mm ± 3.4 mm, and a post-therapeutic mouth opening of 50.4 mm ± 12.8 mm, the patients achieved higher mouth openings compared with the 24 patients with improved or resolved pain symptoms, but a considerably lower rate of change. The remaining patients showed a maximum mouth opening of 42.5 mm ± 9.5 mm pre-therapeutically and a maximum mouth opening of 47 mm ± 8.6 mm post-therapeutically, resulting in an overall median movement increase of 6.7 mm. The refractory patients thus showed only 38% of the increase in mobility of the patients with improved or resolved pain symptoms.The visual analog scale of the patients revealed unchanged pain symptoms in five patients and noticeable improvement in 24 patients, where 17 were completely pain free concerning the masticatory muscles and temporomandibular joints at re-evaluation. None of the respondents indicated worsening pain .The present study showed a significant increase in maximum mouth opening and right condylar motion in patients with diagnosed myofascial pain (RDC/TMD I.a and I.b) after three months of Michigan splint therapy. Furthermore, 24 of the 29 patients reported a significant decrease in pain symptoms, and 17 patients experienced complete remission according to verbal analog scale assessment. None of the patients showed a worsening of symptoms. When classifying these results, it must be discussed that the use of scales involves individual and qualitative data from the patients. Not least for this reason, an adjuvant quantitative analysis of the treatment success was carried out. However, current studies on test reliability, validity, and minimal detectable change as well as correlations of demographic variables with comparable scales come to the conclusion of an excellent test reliability of comparable scales . FurtherThe results of the present study indicate the positive effects of Michigan splint therapy, which was able to achieve substantial relief of myofascial pain in the majority of cases within a relatively short treatment period. The applied ultrasound facebow technique proved to be a valuable addition for both the study objective and for visualization on the patient and the confirmation of the diagnosis.


The results suggest that subjects’ reaction to an intra-oral cold stimulation of the oral mucosa can serve as a potential tool to foretell postoperative dental pain following restorative dental procedures.Pain prevention and management is one of the primary goals of dental care. Postoperative dental pain (PDP) following caries removal and performance of a restorative dental treatment is a common clinical phenomenon, often causing significant discomfort to dental patients. In the present study, a psychophysical non-invasive method, qualitative sensory testing , was used in an attempt to foretell PDP following dental restorative procedures. Forty-two dental patients underwent an intra-oral cold QualST four times: immediately prior to a restorative dental procedure and at a follow-up meeting 1–3 weeks later, on the treated and on the contralateral oral sides. The QualST measures included subjects’ evaluation of the magnitude of pain and cold sensations experienced  and the duration of the cold sensation (in seconds). Additional measures included age, gender, level of dental anxiety, jaw treated, and type of dental restoration performed (Class I or Class V). Subjects’ PDP was assessed through the phone using numeric rating scales 24, 48, and 72 h postoperatively. The highest level of PDP experienced by subjects occurred 24 h postoperatively (ANOVA with repeated measures). Of the study variables, the QualST pain sensation (B = 0.645,  Postoperative dental pain (PDP) is a common phenomenon . It has Being a subjective experience, quantifying pain in a standardized way is important to obtain a broader assessment other than self-report with respect to cultural and ethnic diversity . One psySimilar to other psychophysical evaluations, QST uses quantitative mechanical, electrical, thermal (cold/heat), or chemical stimuli applied to the skin, muscle, or mucosa ,11,12,13On the oral mucosa, QST has been proven to be stable and reliable in assessing somatosensory function in healthy volunteers, special pain populations, and patients ,16,17. TBaad Hansen et al., showed that simple clinical alternatives ), such as the use of a cotton swab to apply touch stimulus, the use of stainless-steel dental spatula to apply cold stimulus, or the use of a dental examination probe to apply pinprick stimulus, show sufficient inter- and intra-examiner reliability and can be used as a screening method . Zaguri Therefore, the aim of the present study was to describe and validate the IT-QualST as a mode to foretell post-procedural pain related to dental restorations.Patients were recruited from the dental clinics of senior dental students at the School of Dental Medicine, Tel Aviv University. Informed consent was obtained from all participants. This study received the approval of the ethical committee of Tel-Aviv University .Inclusion criteria were age over 18 years and a need to receive an initial Class I or Class V restoration  with no gingival inflammation and/or recession and with an intact contra lateral tooth.Exclusion criteria were teeth with previous restoration(s), teeth with gingival recessions, restorations of extensive carious lesions, and restorations that required the use of a matrix band. Additionally, patients who reported using analgesic medications prior to or post dental treatment were excluded from the final calculations.Restorations were performed by senior dental students under close supervision of their clinical instructors. All procedures were strictly standardized, and students were requested to obtain approval after each and every one of the steps involved in the clinical procedure . The restoration was performed under local anesthesia with the use of composite resin. The restorative procedure included cleaning the cavity with a cavity cleaner  and the use of etching and bonding . Restoration in which one (or more) of the procedural steps was not approved by an instructor was not included in the study. All the patients had previous experience with dental care.The following general information regarding participants was collected: gender, age, jaw treated (maxilla/mandible), sort of restoration (Class V/Class I), use of medications (prior and/or post treatment), and level of dental anxiety. The latter was included in this study to evaluate the possible influence of fear and anxiety on subjects’ perception and report of pain.In total, 55 patients were approached and requested to participate in the study. Three subjects declined due to fear of pain, two were excluded due to medical conditions that can affect pain perception, and four were excluded due to the use of analgesic drugs prior to treatment (84% response rate). Five subjects were excluded from the study as the performed restoration did not reach dentin and five subjects due to the use of analgesic drugs post treatment (some overlapping between the excluded groups exists). The final study population comprised 42 patients.Subjects’ level of dental anxiety was assessed through the Dental Anxiety Scale (DAS) . DAS wasAs subjects’ ability to process relevant information in a stressful clinical situation might be impaired , communiThe IT-QualST protocol was used as described by Zaguri et al. . A cottoEach site underwent two cold stimulations, on two different occasions, as described below. The sequence of the swab application was the treated side/contralateral side on the first encounter and vice versa on the second encounter .One investigator (DA) performed all the tests. Prior to the experiment, the procedure of swab spraying with ethyl chloride, swab application, and measurement of the cold sensation duration (see below) was practiced on 11 subjects. As the same examiner performed all the tests, the purpose was to practice and standardize the examiner’s skills in order to achieve maximal intra-examiner reliability. These subjects were not included in the final study.Subjects were requested to rate the intensity of sensation felt  and the duration of the cold sensation as follows.The pain and cold sensations were rated using a 10 cm visual analogue scale (VAS). The minimum and maximum possible sensations were defined as “no sensation” and “freezing cold” for cold, and “no pain” and “worst possible pain” for pain. The duration of the cold sensation after the removal of the stimulus (in seconds) was recorded using a stopwatch.Pain-treated1), sensation of cold (Cold-treated1), and duration (in seconds) of the cold sensation (Time-treated1).On the treated side, immediately prior to the planned restorative treatment. Patients rated the sensation of pain (Pain-CL1), sensation of cold (Cold-CL1), and duration (in seconds) of the cold sensation (Time-CL1).On the contralateral (CL) side, immediately prior to treatment. Patients rated the sensation of pain (Pain-treated2), sensation of cold (Cold-treated2), and duration (in seconds) of the cold sensation (Time-treated2).On the treated side at a follow-up meeting, 1–3 weeks later. Patients rated the sensation of pain (Pain-CL2), sensation of cold (Cold-CL2), and duration (in seconds) of the cold sensation (Time-CL2).On the contralateral side at a follow-up meeting. Patients rated the sensation of pain  24 h; (ii) 48 h; and (iii) 72 h.24currentPDP, 48currentPDP, and 72currentPDP.What is the level of pain you feel at the treated side at the moment? (NRS ranging from 0—no pain whatsoever to 10—unbearable pain). Results were marked as: 24worstPDP, 48worstPDP, and 72worstPDP.What was the level of the worst pain you experienced in the treated area in the last 24 h? (NRS as above). Results were marked as: At each of above time points, patients were contacted via phone and requested to respond to the following questions:A flowchart of the study protocol is presented in The reliability of the IT-QualST measures was assessed through Cronbach’s alpha and Pearson correlation coefficients.ANOVA with repeated measures  was used to compare among PDP at different time points .Stepwise linear regression was used to identify possible predictors of the highest level of PDP experienced by patients.n = 55) was approached in order to allow for the loss of some of the subjects.Power analysis showed that 14 subjects enabled a power of 0.9 in order to achieve a Pearson correlation of 0.75, at a significance level of 0.05, between two normally distributed variables. A bigger group . The final study population comprised 42 patients . Subjects’ level of dental anxiety (DAS) was 8.82 ± 4.03.In total, 59.5% of the performed restorations were in the mandible and 53.7% were Class V. Details about the subjects’ age, type of restoration, and jaw in which the restoration was performed (upper or lower), according to gender, are presented in The mean values (±SDs) of subjects’ pain, cold, and cold duration assessments, in the different oral areas (treated side vs. CL side) and at different time points (immediately prior to restoration—first meeting—and at follow-up—second meeting), are presented in p < 0.05).No differences could be observed between the treated and CL sides, nor between the first and second meetings. Additionally, no differences were found between the cold assessments  nor between the cold duration evaluations . No differences were found between Pain-treated1 and Pain-CL1 Pain : Cronbach alpha = 0.84.(ii)Cold : Cronbach alpha = 0.93.(iii)Cold duration : Pearson correlation coefficients ranging 0.75–0.80.The reliability of the pain, cold, and cold duration measures was as follows:As the reliability of the three IT-QualST measures was high, it was decided to use only the measures of the treated side prior to treatment  for further analyses.t-test).As expected, the highest levels of current and worst PDP were recorded 24 h postoperatively  = 10.26 and 31.93, respectively, p < 0.000 for both) (ANOVA with repeated measures showed a significant effect of time for both current and worst PDP (For both) . The higWhen the ANOVA calculations were adjusted for dental anxiety and gender , some differences between genders could be observed. While the general pattern remained unchanged , some differences between genders could be observed .The PDP scores reported by the patients in the present study were rather low (ranging from 0 to 1.83). Therefore, it was decided to examine the factors that could predict the highest level of PDP experienced by patients, namely, their worst PDP 24 h postoperatively. A stepwise linear regression was used to identify possible predictors of 24worstPDP.Initially, the following candidate variables were entered into the equation: type of restoration (Class I or Class V), jaw treated (maxilla or mandible), Pain-treated1, Cold-treated1, Time-treated1, age, gender, and DAS.As gender was shown to have a significant effect on pain in the dental setting , an inteOn a second step, in an effort to increase the predictive ability of the model, interactions between DAS and each one of the three IT-OualST measures were omitted from the calculation.Variables entered into the equation were: type of restoration (Class I or Class V), jaw treated (maxilla or mandible), Pain-treated1, Cold-treated1, Time-treated1, age, gender, DAS, and an interaction between DAS and gender (DAS*gender). Under such conditions, variables that emerged as possible predictors of 24worstPDP were Pain-treated1, Time-treated1, and the DAS*gender interaction b.In clinical practice, QST and QualST are used to apply quantitative and qualitative stimuli  to a variety of tissues , and to use psychophysical methods such as threshold determination or establishing stimulus–response function to assess the function and integrity of the somatosensory system .Cruz-Almedia et al.  suggesteThe use of cold stimuli to test pain sensitivity is not a new concept in pain medicine ,13,34,35Previous studies showed that standardized intraoral QST measures have good inter-examiner and test-retest reliability , with noMost of the studies that have used QST protocols inside the oral cavity have been tested in some chronic dental and oral pain conditions to test for dysfunction in nerve conduction ,18. The The protocol used in the present study was as described by Zagury et al. . AlthougThere are relatively few reviews on age-related changes in the pain sensitivity response. A meta-analysis by Lautenbacher  suggesteIn addition, the PDP reported by patients in the present study was also rather low . Briso et al.  showed tSome of the factors that may affect subjects’ experience and report of pain are gender and anxiety. Fear of pain and anxiety sensitivity have consistent influences on pain ratings . AnxiousPrevious publications have shown that dental anxiety (DAS) is usually higher among women compared to men ,47,48. TThere is evidence that social models  and earlThe finding that subjects’ sensations, such as the reaction to cold stimulation of the oral mucosa, are significantly associated with the highest PDP experienced 24 h after a restorative procedure is intriguing. The oral mucosa is regarded as a highly developed and specialized sensory system . It can Effective and safe pain management should be the primary goal of each dental practice. In an era of personalized medicine, it is still an enigma as to which patients will experience PDP. The possibility of using an available, simple, and reliable clinical test for this purpose bears promise. A better understanding of the potential of developing PDP will help clinicians prevent it and better prepare their patients .In the present study, all clinical procedures were carried out by dental students under close supervision and with the use of standardized techniques, a fact that might have mitigated some of the possible confounding factors. The minimal size of the restorations could have further minimized the effect of operator variability  on PDP. Subjects’ reaction to intra-oral cold stimulation of the oral mucosa can serve as a potential tool to foretell postoperative dental pain following restorative dental procedures. The ability to predict patients who are prone to experiencing PDP will enable clinicians to apply personalized medicine, such as a selective prescribing of postoperative analgesic drugs to certain patients and the avoidance of overprescribing of drugs to patients whose proneness to experiencing PDP is low.


Oxycodone hydrochloride is a semisynthetic narcotic analgesic agent. This study aimed to explore optimal titration strategy of controlled-release (CR) oxycodone hydrochloride in patients with cancer pain.258 patients, who used regular strong opioids (morphine and CR oxycodone hydrochloride) for cancer pain across 25 three grade class hospitals in China during January 15th 2017 to April 30th 2017, were retrospectively studied. The patients were divided into 4 groups according to treatment regimens titrated. The pain remission rate and numeric rating scale (NRS) of cancer pain was recorded at 0, 12, 24, 36, 48, 60, 72 h after opioid titration. The incidence of adverse events (AEs) with therapy were also observed.P < 0.001) than Group A. For the complete remission rate, there were also significant differences among the four groups (P < 0.001). No significant difference was found among four groups for pain remission rate at 24, 72 h after treatment. Multiple comparison of NRS scores showed that the both Group B and C varied significantly with Group D , showing superior analgesic effect over Group D. AEs were significantly different among groups (P < 0.01), with the most frequent AEs in Group A, lowest in Group B.12 h after treatment, pain remission rate of Group B, C and D was significantly higher (The rapid titration strategy of background CR oxycodone hydrochloride was effectiveness and safety in patients with moderate-to-severe cancer pain. According to World Health Organization (WHO) guidelines, the dose of opioid drugs can be titrated upward in management of chronic, moderate to severe cancer pain, until an acceptable balance between analgesia and side effects. Hence, the initiation and titration of an opioid for moderate to severe pain is a critical point during individual patient treatment. According to the guidelines of the European Society for Medical Oncology (EMSO), opioid should be titrated as rapidly as possible to take effect. Morphine remains the traditional choice for opioid agonists. However, it may be difficult to find an optimal initial dose, due to the great variation of oral bio-availability of morphine 15–64%) in individual patient, and relatively high incidence of side effects, especially in treatment beginning 5–64% in .Oxycodone hydrochloride is a semisynthetic narcotic analgesic agent. It has been used since 1917 with a clinical impression, due to it is as effective as morphine, with fewer side effects. Oxycodone is also available in a single-entity CR formulation for treatment of moderate to severe pain. CR opioid formulation offers advantage of convenient dosing schedule for around-the clock analgesia. However, it has significantly longer duration of pain remission than that provided by the immediate-release (IR) formulation . In addiIR morphine has been recommended in a dose titration procedure to achieve rapid onset during pain management . Then, iThere was no consensus regarding the dose titration of oxycodone. When titrating with background CR oxycodone, many clinicians adjusted the subsequent dose, according to the frequency of pain episodes, rescue medication, or the intensity of pain in previous 12 h after treatment. In order to quickly adjust the opioid to appropriate dose and quickly relieve the patient's pain, this study adjusted the amount of CR oxycodone to 12 h after the first dose. Therefore, this retrospective study aimed to identify the optimal titration strategy of CR oxycodone as background dose to achieve adequate pain remission in patients with moderate to severe cancer pain.Two hundred and fifty-eight patients, who used regular strong opioids (morphine and CR oxycodone hydrochloride) for cancer pain across 25 three grade class hospitals in China during January 15th 2017 to April 30th 2017, were retrospectively study. The patients were eligible for enrolment if they (1) aged 18–80 years; (2) histologically or cytologically confirmed diagnosis of cancer; (3) moderate to severe pain with Numeric Pain Scale Ratings (NRS) ≥4; (4) had ability to understand and communicate with the doctor regarding the treatment regimen. Patients were excluded if they (1) had neuropathic pain; (2) was pregnant or breastfed in women with childbearing potential; (3) had an oncologic emergency; (4) showed some contraindication to the use of strong opioid; (5) major liver and kidney function impairment ; (6) had a history of alcohol or drug abuse.The administration of baseline opioids for pain management was checked in each case, and patients were divided into 4 groups according to treatment regimens.Patients were initially titrated with IR morphine 4 hourly, and were reassessed according to response of the patients and performed dose titration every 60 min. The starting dose was determined by the treating physician according to international guidelines, and titrated until adequate pain control was achieved. At this stage, patients were switched to equianalgesic oxycodone.® Tablets, Bard Pharmaceuticals Limited, UK) were 10 or 20 mg, respectively, every 12 h. For opioid-tolerant patients, the initial dose of oxycodone was equivalent to 1/2 of total opioid taken in the previous 24 h. When the frequency of rescue medication ≥2 in the previous 12 h, 10 mg of oxycodone was added to the current regular dose at 12, 24, 36, 48, 60, and 72 h after treatment. When the frequency of breakthrough pain episodes < 2 in the previous 12 h, the current dose was repeated.For opioid-naïve patients, whose pain intensity is moderate or severe, the doses of oxycodone hydrochloride CR tablets  taken in the previous 12 h plus initially regularly scheduled oxycodone dose.When the intensity of breakthrough pain was ever higher than 7 (NRS) in the previous 12 h, the subsequent dose was increased by 50–100% at 12, 24, 36, 48, 60, and 72 h after treatment. If higher than 4 (NRS), the subsequent dose was increased by 25–50%.Information was gathered from patients' electronic medical record, including general demographic data (age and gender), cancer status (site and metastasis), analgesic therapy, NRS score at 0, 12, 24, 36, 48, 60, and 72 h after opioid titration.The pain intensity of each patient was evaluated by a numeric rating scale from 0 to 10, in which 0 indicates no pain at all, and 10 indicates the worst imaginable pain that cannot be tolerated. Pain remission rate was defined as the rate of patients with NRS score ≤ 3 [CR (Complete remission)] or achieving a reduction of 25% when NRS score >3 [PR ] at 24 h.The pain remission rate at 12, 24, and 72 h was evaluated. In addition, the NRS score during 72 h after opioid titration, the frequency of rescue medication during opioid titration period, and the incidence of clinical side effects associated with therapy, including constipation, nausea, and dizziness, were also observed.t-test or non-parametric Mann–Whitney U test for continuous variables. We examined the primary aim, using a linear mixed model for repeated measures. For outcomes with significant difference at baseline, it was adjusted for confounders to obtain the estimated marginal means (EMM) with standard error (SE). A P-value of < 0.05 was considered as statistically significant.Statistical analyses were performed using SPSS, version 17.0 . Baseline comparisons were performed using chi-square test or Fisher's exact test for categorical variables and P > 0.05). However, it showed significant differences with respect to smoking, bone metastasis, pain pathology and baseline NRS score among group (P ≤ 0.001). Correlation analysis showed that smoking, bone metastasis and pain pathology were associated with NRS score.A total of 258 cancer patients were included in this retrospective study. Demographics of the patient population are shown in P < 0.001) than Group A , and complete remission rate of Group B (69.72%), Group C (58.14%) was significantly higher than Group A (22.22 %) (P = 0.0022), and complete remission rate of Group B was also significantly higher than Group D . After treatment for 24 h, 85.0% (204/240) patients titrated with background CR oxycodone had pain remission, and 71.4% (13/18) patients titrated with IR morphine had pain remission. Among the four groups, no significant difference was found in term of pain remission rate at 24 h . However, there were significant differences in complete remission rate among the four groups (P = 0.049). Patients who titrated with CR oxycodone as baseline opioid in group B had a higher rate of complete remission than patients in group D (P = 0.007) (P > 0.05).After treatment for 12 h, pain remission rate of Group B (77.06 %), Group C (65.12%), and Group D (59.77%) was significantly higher  . After tP < 0.05), covariance analysis was performed. The NRS score in each group showed a decline trend over time , and had a superior analgesic effect over Group D. The superiority of Group B and Group C also could be observed from estimated marginal means for the NRS score when compared Group A , and the difference did not attain statistical significance .Considering the significant difference of NRS score at baseline (ver time . For eacP < 0.001) (P < 0.001).In order to explore the correlation between pain pathology and the effectiveness of opioid analgesia, we analyzed the relationship between pain pathology and NRS score. It found that compared to the nociceptive pain group, the mixed pain group was associated with higher NRS score (< 0.001) . TherefoAmong the four groups, there was no significant difference in terms of the frequency of rescue medication during 0–12, 12–24, 24–36, 36–48, 48–60, and 60–72 h after treatment, respectively. While, except for Group A, there were significant difference in term of the frequency of rescue medication among different time periods after treatment  in group B, C and D (P < 0.05), and showed an overall declining tendency as administration time extended . At 24 hP < 0.0001), and Group A has the most frequent AEs.Of the 390 total AEs that occurred during open-label titration, most (96.2%) were mild or moderate in intensity. Severe adverse events occurred in 16 (4.1%) patients. A summary of AEs according to successful titration is presented in The European Association for Palliative Care (EAPC) guidelines recommended that IR and slow-release oral formulations of morphine, oxycodone, and hydromorphone can be used for dose titration. The titration schedules for both types of formulation should be supplemented with oral IR opioids given as needed . In termP < 0.001) than that titrated with IR morphine (22.22 % for Group A). This means that CR oxycodone could achieve rapid analgesic effect  was significantly higher (P = 0.049). Patients who titrated with CR oxycodone as baseline opioid in group B had a higher rate of complete remission than patients in group D (P = 0.007). Opioids are the current standard treatment of moderate or severe nociceptive pain, while neuropathic pain or mixed in origin is generally considered to be a little resistant to opioids , and had a superior analgesic effect over Group D, which may be attributed to the significantly higher proportion of patients with mixed pain in Group D (55.7%) than that of Group B and Group C  (P < 0.001). The superiority of Group B and Group C can also be observed from estimated marginal means for the NRS score when compared with Group A, and the difference did not attain statistical significance .Clinical outcomes of opioids titration for cancer pain are particularly critical on the first day, and the rapid and stable analgesia can not only reduce the pain symptoms of patients, but also increase the patient confidence in the subsequent treatment. In this study, at 24 h after treatment, 84.8% (219/258) of the patients had pain remission, and 75.2% (194/258) of the patients had complete remission. Wasaburo Koizumi et al. have reported that the pain remission rate at 24 h after the initial CR oxycodone intake (starting with a 5 mg CR oxycodone every 12 h and the dose could be titrated against the intensity of pain) was 70% (95% CI 45.7–88.1) . The ove opioids . Result P < 0.01), with the most frequent AEs in Group A. There are two major advantages in adjusting the CR oxycodone hydrochloride dose every 12 h. On one hand, titration with IR morphine for breakthrough cancer pain exist major limitations. This method are the intricate multiple dose schedule, including the nighttime or double bedtime doses, the appropriateness of IR morphine for breakthrough pain and the need to modify drug formulation as well as administration timing once titration to pain remission is reached , or the total amount of rescue doses (Group C) may provide better analgesia than that according to the intensity of breakthrough pain (Group D). It appears that adjusting the CR oxycodone hydrochloride dose every 12 h may achieve rapid and stable analgesic effects. A large-scale clinical trial on rapid pain control is need in the future to find a better CR background titration strategy that provide more clinical benefit for cancer patients.The original contributions presented in the study are included in the article/Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.WeiF and YW conceived the study. FR, YM, HZ, QW, WLin, ZW, JH, WLia, TZ, QC, and WX performed the literature search and writing of the manuscript. TY, JY, SM, YS, LM, CL, and SZ analyzed and interpreted the data. DZ, SW, HL, WenF, and JL collected and assembled the data. MW submitted the manuscript and is the corresponding author. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.