Pharmacological and clinical aspects of immediate release fentanyl preparations: Criteria for selection

In palliative care, pain management is often hampered by episodes of breakthrough pain, characterised by a rapid onset and, on average, duration less than 1 h. Until recently, only immediate release morphine and oxycodon preparations were available for the treatment of these episodes but time until effect is too long for both of these drugs. Recently, immediate release fentanyl products have become available for the treatment of breakthrough pain. These products can be classified as oromucosal and nasal products. Both are absorbed rapidly by the mucosa, although the oromucosally delivered products are partly absorbed by the gastrointestinal tract and therefore reach maximum plasma levels somewhat slower (after 30-90 min) than the nasally delivered products (after ~15 min). In clinical placebo controlled studies, all new immediate release fentanyl products were proven to be effective from 15 min after administration in the treatment of breakthrough pain. The first studies comparing immediate release fentanyl with immediate release morphine or oxycodon also found superiority for the new fentanyl products

Treatment with subcutaneous and transdermal fentanyl: Results from a population pharmacokinetic study in cancer patients

Purpose: Transdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we studied the pharmacokinetics of subcutaneous and transdermal fentanyl. Furthermore, we evaluated rotations from the subcutaneous to the transdermal route. Methods: Fifty-two patients treated with subcutaneous and/or transdermal fentanyl for moderate to severe cancer-related pain participated. A population pharmacokinetic model was developed and evaluated using non-linear mixed-effects modelling. For rotations from subcutaneous to transdermal fentanyl, a 1:1 dose conversion ratio was used while the subcutaneous infusion was continued for 12 h (with a 50 % tapering after 6 h). A 6-h scheme with 50 % tapering after 3 h was simulated using the final model. Results: A one-compartment model with first-order elimination and separate first-order absorption processes for each route adequately described the data. The estimated apparent clearance of fentanyl was 49.6 L/h; the absorption rate constant for subcutaneous and transdermal fentanyl was 0.0358 and 0.0135 h-1, respectively. Moderate to large inter-individual and inter-occasion variability was found. Around rotation from subcutaneous to transdermal fentanyl, measured and simulated plasma fentanyl concentrations rose and increasing side effects were observed. Conclusions: We describe the pharmacokinetics of subcutaneous and transdermal fentanyl in one patient cohort and report several findings that are relevant for clinical practice. Further research is warranted to study the optimal scheme for rotations from the subcutaneous to the transdermal route

Reduction in potentially inappropriate end-of-life hospital care for cancer patients during the COVID-19 pandemic:A retrospective population-based study

Background: The COVID-19 pandemic impacted cancer diagnosis and treatment. However, little is known about end-of-life cancer care during the pandemic. Aim: To investigate potentially inappropriate end-of-life hospital care for cancer patients before and during the COVID-19 pandemic. Design: Retrospective population-based cohort study using data from the Netherlands Cancer Registry and the Dutch National Hospital Care Registration. Potentially inappropriate care in the last month of life (chemotherapy administration, &gt;1 emergency room contact, &gt;1 hospitalization, hospitalization &gt;14 days, intensive care unit admission or hospital death) was compared between four COVID-19 periods and corresponding periods in 2018/2019. Participants: A total of 112,919 cancer patients (⩾18 years) who died between January 2018 and May 2021 were included. Results: Fewer patients received potentially inappropriate end-of-life care during the COVID-19 pandemic compared to previous years, especially during the first COVID-19 peak (22.4% vs 26.0%). Regression analysis showed lower odds of potentially inappropriate end-of-life care during all COVID-19 periods (between OR 0.81; 95% CI 0.74–0.88 and OR 0.92; 95% CI 0.87–0.97) after adjustment for age, sex and cancer type. For the individual indicators, fewer patients experienced multiple or long hospitalizations, intensive care unit admission or hospital death during the pandemic. Conclusions: Cancer patients received less potentially inappropriate end-of-life care during the COVID-19 pandemic. Because several factors may have contributed, it is unclear whether this reflects better quality care. However, these findings raise important questions about what pandemic-induced changes in care practices can help provide appropriate end-of-life care for future patients in the context of increasing patient numbers and limited resources.</p

Influence of aprepitant and localization of the patch on fentanyl exposure in patients with cancer using transdermal fentanyl

__Background and Objectives:__ The cutaneous fentanyl patch is widely used to treat continuous pain in patients with cancer. Its use is hampered by a high inter- and intrapatient pharmacokinetic variability. Factors that influence this pharmacokinetic variability are largely unclear. The aim of these studies was to test if common patient variables, i) the use of the moderate CYP3A4 inhibitor aprepitant and ii) the localization of the fentanyl patch (upper arm versus thorax) influence systemic exposure to fentanyl in patients with cancer using a transdermal fentanyl patch. __Results:__ The AUC0-6 h of fentanyl was 7.1% (95% CI: -28% to +19%) lower if patients concurrently used apre

Effects of smoking and body mass index on the exposure of fentanyl in patients with cancer

The transdermal fentanyl patch is widely used to treat cancer-related pain despite its wide inter- and intrapatient variability in pharmacokinetics. The aim of this study was to investigate whether smoking and body size (i.e. body mass index) influence fentanyl exposure in patients with cancer. These are factors that typically change during treatment and disease trajectories. We performed an explorative cohort study in patients with cancer using transdermal fentanyl patches (Durogesic®), by taking a blood sample for pharmacokinetic analysis one day after applying a patch in patients with a stable fentanyl dose. A total of 88 patients were evaluable. Although no statisticall

Perceptions of involvement in advance care planning and emotional functioning in patients with advanced cancer

Purpose: Advance Care Planning (ACP) is positively associated with the quality of care, but its impact on emotional functioning is ambiguous. This study investigated the association between perceptions of ACP involvement and emotional functioning in patients with advanced cancer. Methods: This study analyzed baseline data of 1,001 patients of the eQuiPe study, a prospective, longitudinal, multicenter, observational study on quality of care and quality of life in patients with advanced cancer in the Netherlands. Patients with metastatic solid cancer were asked to participate between November 2017 and January 2020. Patients’ perceptions of ACP involvement were measured by three self-administered statements. Emotional functioning was measured by the EORTC-QLQ-C30. A linear multivariable regression analysis was performed while taking gender, age, migrant background, education, marital status, and symptom burden into account. Results: The majority of patients (87%) reported that they were as much involved as they wanted to be in decisions about their future medical treatment and care. Most patients felt that their relatives (81%) and physicians (75%) were familiar with their preferences for future medical treatment and care. A positive association was found between patients’ perceptions of ACP involvement and their emotional functioning (b=0.162, p<0.001, 95%CI[0.095;0.229]) while controlling for relevant confounders. Conclusions: Perceptions of involvement in ACP are positively associated with emotional functioning in patients with advanced cancer. Future studies are needed to further investigate the effect of ACP on emotional functioning. Trial registration number: NTR6584 Date of registration: 30 June 2017 Implications for Cancer Survivors: Patients’ emotional functioning might improve from routine discussions regarding goals of future care. Therefore, integration of ACP into palliative might be promising

Impact of infection on proteome-wide glycosylation revealed by distinct signatures for bacterial and viral pathogens

Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection

Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study

BackgroundThe PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice.MethodsFebrile children and controls were recruited on presentation to hospital in 9 European countries 2016-2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed.FindingsOf 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92-5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07-7.59), Group A streptococcus (OR 2.73, 95% CI 1.13-6.09) and E. coli (OR 2.7, 95% CI 1.02-6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11-0.46), influenza B (OR 0.12, 95% CI 0.02-0.37) and RSV (OR 0.16, 95% CI: 0.06-0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23-0.72) and EBV (OR 0.71, 95% CI 0.56-0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively.InterpretationMost febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics.FundingEU Horizon 2020 grant 668303