We continue to make good progress across Workpackages, despite the impact of the Covid pandemic.
WP1- Project management. 2 SC and 1 GA meetings were successfully held, also with the SEAB. The PMO held frequent TCs to monitor progress of the project (with the SC) and to prepare the outline and minutes of the meetings and maintained regular communication with the EC. Bi-weekly TC were held with the coordinator. The QSPainRelief intranet KEYWAYS keeps all documents and information on Milestones & Deliverables. A no-cost extension was prepared and submitted.
WP2- QSPainRelief model platform development. Neural circuit models for analgesia, abuse liability, sedation & cognitive impairment all have their advanced versions. The LeiCNSPK3.0 and LeiCNSBK1,0 models predicted CNS target site concentrations and target-binding kinetics) for ~100 opioids and augmentation drugs, for different doses, for use in the neural circuit models.
WP3- Data collection and data management. The updated DMP and database were reviewed and improved. Historical clinical data and collected data on plasma pharmacokinetics, CNS receptor expression and receptor occupancy data of our selected drugs, and data produced by WP5, WP6, and WP7 are in part uploaded, and the newer data are in the process of being uploaded.
WP4- In silico computations and risk benefit analysis. Lack of physiological patient data (WP8) restricted further development of the CUI model. Instead, an online patient questionnaire was developed. Data on preferences on (side) drug effects will be collected and used. ,Also, a draft CUI Shiny app (in R software) is designed that allows interactive adjustment of weights and stratifications and easy communicating and sharing of results and alternative outcomes. The MVR model is ready to analyse clinical data.
WP5- Cellular signalling and pathway analysis. The in silico predicted existence of MOR-CB1 heteromers was demonstrated to exist in vitro. In silico approaches (further) assessed time dependency of receptor binding kinetics, allosterism, cooperation and formation of heteromers. In vitro work was performed on mRNA target expression and signal transduction differences, for control, and acute and chronic morphine exposure, with/without THC..
WP6 – Preclinical in vivo validation of QSPainRelief predictions. Studies with morphine +/`pregabalin and morphine +/- THC in male and female control and neuropathic pain mice are completed. A decrease of self-administration by morphine +/- THC, indicated a sedative effect of morphine. Studies for morphine +/- fluvoxamine are in progress.
WP7- Clinical efficacy and adverse effects of analgesic treatments in healthy subjects. QSPainRelief-novelB with nociceptive tests, and a CNS test battery on cognition and neurophysiology in healthy volunteers with morphine + fluvoxamine was completed. Collected data re currently being processed.
WP8- Calibration and evaluation of the QSPainRelief platform using CNS biomarkers in real world patients. QSPainRelief-patientCNS was impacted by the covid pandemic (also post pandemic). The number of patients had to be reduced, and in today’s clinical practice drug combinations are exceptional, so recruitment criteria were adapted to single drug treatment. Alternative sources of clinical data is further searched on. A complementary clinical study in patients about to undergo thoracotomy was performed to study. mechanisms contributing to the development of persistent pain after surgery. The REDcap platform for online data collection was setup, including online versions of all questionnaires
WP9- Dissemination, Training and Exploitation. QSPainRelief’s social media presence kept active. The website was maintained. QSPainRelief partners gave multiple lectures and poster presentations at scientific meetings, and 7 new papers were published, A patient event was held. One new masterclass was held and recorded (website, YouTube channel). Two mentor-mentee sessions were held. Frequent ECS journal club meetings were held. The IIB updated the exploitation plan to be discussed soon.
WP10- Ethical considerations. The 3rd Interim report on ethics monitoring for pre and clinical studies was finalized. QSPainRelief received authorization to perform a) clinical QSPainRelief-PatientsSTRAT study in WP8; b) preclinical studies in WP6; and c) clinical NovelB study in WP7. SEAB members were invited to the 5th GA meeting, and each periodical SC TCs, and provided regular feedback on the QSPainRelief work.
WP11- Ethics requirements. Nearly all ethical requirements were fulfilled in time already in previous periods (one deliverable is pending).
