Work Packages

QSPainRelief consisted of 10 central work packages (WPs) that interacted with each other. The output of four core areas has been crucial to the success of the project. Those were the mechanistic & modelling area (WP2, WP4, and WP5), which ultimately led to the decision on which drug combinations were tested in the preclinical & clinical validation studies (WP6, WP7, and WP8), central data management of both the model data and the empirical data (WP3), and well-targeted, high-impact dissemination of objectives and results (WP9). All activities were guided and overseen by WP1 (Project management) and WP10 (Ethics).

• WP1 - Project management

  Lead: Universiteit Leiden (ULEI)

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  Effective project management is a central element of successful research. This is because large research projects entail a lot of administrative work. The following objectives were actively pursued by WP1:

  • Make QSPainRelief achieve its objectives by delivering its milestones and deliverables in high quality, in time, and within the given budget
  • Help the consortium abide by the regulations and contractual obligations according to the grant agreement, its annexes, and the consortium agreement
  • Look after the project’s finances and report them properly to the European Commission
  • Establish a communication infrastructure which enables the partners to communicate efficiently and to stay connected for the run-time of the project
  • Preserve the rights of the partners regarding intellectual property, and act as a mediator in case of disputes
• WP2 – QSPainRelief model platform development

  Lead: In Silico Biosciences, Inc. (ISB)

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  The overall aim of this WP was to develop a computer-based Quantitative Systems Pharmacology (QSP) PainRelief Model Platform to predict the best combinations of an opioid/analgesic combined with a drug approved for other indications to improve analgesia and decrease side effects (drug abuse liability, sedation, and cognitive impairment) in patients with chronic pain. The best drug combinations underwent utility analysis to select two drug combinations (selected opioid + compound A, selected opioid + compound B) that were prospectively tested in healthy volunteers and in chronic pain patients. The specific objectives of WP2 were:

  • Develop a predictive QSPainRelief model for analgesia in healthy volunteers and patients with chronic pain
  • Develop a predictive QSPainRelief model for drug abuse liability in healthy volunteers and patients with chronic pain
  • Develop a predictive QSPainRelief model for sedation & impaired cognition in healthy volunteers and patients with chronic pain
  • Identify the optimal drug combination for a preclinical study in a) a self-operant mouse model and b) clinical studies in both healthy volunteers and in patients with chronic pain
  • Develop a clinical trial design to prospectively validate this combination in a population of patients with chronic pain
• WP3 – Data collection and data management

  Lead: Universiteit Leiden (ULEI)

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  The overall aim of WP3 was the careful collection of the data relevant for use (parameterisation, calibration, and validation) in the predictive models and interpretation of the modelling results, as well as the collection of the model outputs. WP3 had the following specific objectives to achieve the overall aim:

  • To achieve good data management according to the FAIR principles
  • To collect data and model output in a transparent and structured way
  • To provide access to the data for all participants
  • To prepare the data for dissemination
• WP4 – In silico computations and risk-benefit analysis

  Lead: PD-value B.V. (PD-value)

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  Extensive in silico QSPainRelief model computations of the efficacies and safety of an exhaustive series of binary combination drug treatments was performed in WP2, but not ready for full interpretation or decision making, also because of the sheer amount of data. The overall aim of WP4 was therefore to select the top two drug combination therapies (selected opioid with compound A or with compound B) for improved analgesic action and reduced drug liability and sedation & cognitive impairment side effects, based on aggregated multivariate and clinical utility analyses. The specific objectives of WP4 were:

  • To design draft multivariate (MVR) and clinical utility index (CUI) models to aggregate the results of the multi-attributable outcomes from WP3 – available at baseline – in a risk-benefit analysis to help understand the influence of chronic pain, genetic factors, age, and sex
  • To refine the draft model with additional data collected in WP3 for risk-benefit analyses of evaluated treatments, to predict and select the top two “winner”drug combination therapies for preclinical experimental approaches in WP6 and WP7 + WP8
  • Enable sharing of results via appropriate summaries and facilitate interpretation using multivariate outcomes, and publish them via a database as specified in WP3
• WP5 – Cellular signalling and pathway analysis

  Lead: Universitat Autònoma de Barcelona (UAB)

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  WP5 main objective was to investigate the signalling pathways associated with opioid receptors to mechanistically understand the cooperativity effects of drug combinations in increasing opioid analgesia efficacy with lower side effects. The specific objectives were:

  • To investigate opioid receptor expression and function in primary cultures of neuronal cells and sex-stratified mouse organotypic brain slice-cultures under basal conditions and after exposure to opioids, other CNS drugs and drug combinations predicted by the QSPainRelief platform
  • To construct a reliable modelling framework of opioid receptor signalling, including pharmacokinetic and pharmacodynamic aspects of ligand-receptor and receptor-receptor interactions
• WP6 – Preclinical in vivo validation of QSPainRelief predictions

  Lead: Universitat Pompeu Fabra (UPF)

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  The overall objective was to evaluate the analgesic and adverse effects (sedation, cognitive impairment, drug abuse liability) of single drugs and drug combinations in mice models with high translational value, to translate between the human and the mouse QSPainRelief models. UPF has previously validated relevant mice models of analgesia, sedation, cognitive impairment, and abuse liability and had the full equipment and expertise to pursue such studies. The specific objectives were:

  • To determine the most appropriate doses of (the selected opioid in WP2, M1), compound A, and compound B (compound A and compound B as selected by WP4 as best to be combined with the selected opioid) to obtain an optimal improvement of analgesia, and reduction of sedation, cognitive impairment, and drug abuse liability
  • To translate the human QSPainRelief model to a mouse QSPainRelief model (WP2); the selected opioid (WP2, M1) was combined with pregabalin in the novel mouse operant model to assess analgesia, sedation, cognitive impairment, and drug abuse liability with high translational value
  • To assess analgesia, sedation, cognitive impairment, and drug abuse liability for selected doses of the top combinations of the selected opioid + compound A, and the selected opioid + compound B, using a self-operant mouse model
  • To determine drug concentration-time profiles of the opioid, compound A, and compound B in blood plasma and in the brain at different time points after drug administration (pharmacokinetics)
• WP7 – Clinical efficacy and adverse effects of analgesic treatments in healthy subjects

  Lead: Stichting Centre for Human Drug Research (CHDR)

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  In this work package, the main objective was to provide and generate data on the clinical efficacy and adverse effects of the analgesic drug combination. The objective was to provide historical data for thorough model development and to generate new data from healthy volunteers (both men and women) on the clinical efficacy, safety, tolerability and pharmacokinetic parameters of two novel analgesic combinations, compared to placebo. CHDR, being a full-service contract research organisation (CRO) experienced in the support of clinical pharmacological trials, executed the study. To meet the second objective, two clinical trials were performed, called “QSPainRelief-novel-compound-A” and “QSPainRelief-novel-compound-B”. The main objective of the QSPainRelief-novel-compound-A trial was to investigate the clinical efficacy and adverse effects of a novel analgesic combination (selected opioid + compound A) in 24 healthy subjects, compared to each of the two analgesic compounds alone and to placebo. The main objective of the QSPainRelief-novel-B trial was to investigate the clinical efficacy and adverse effects of a novel analgesic combination (selected opioid + compound B) in 24 healthy subjects, compared to each of the two analgesic compounds alone and to placebo. The novel analgesic combinations in the QSPainRelief-novel-compound-A and QSPainRelief-novel-compound-B trials consisted of the selected opioid (WP2) with known analgesic effects in both acute and chronic pain conditions, and compound A or compound B, respectively. The QSPainRelief model shall predict drugs and drug combinations that would have the best analgesic profile, following clinical utility analysis (WP4). Compounds A and B were selected during the project runtime. The specific objectives of WP7 were:

  • To provide historical data on PainCart and NeuroCart outcomes from healthy volunteers exposed to single analgesic drugs
  • To generate new data from healthy volunteers on the clinical efficacy, safety, tolerability and pharmacokinetic parameters of a novel analgesic combination (compound A + opioid) in 24 healthy subjects
  • To generate new data from healthy volunteers on the clinical efficacy, safety, tolerability and pharmacokinetic parameters of a novel analgesic combination (compound B + opioid) in 24 healthy subjects
• WP8 – Calibration and evaluation of the QSPainRelief platform using CNS biomarkers in real world patients

  Lead: Université Catholique de Louvain (UCL)

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  Calibration of the QSPainRelief platform required patient data on how different drug combinations affect the central processing of nociceptive input, how they affect the CNS networks underlying drug-induced adverse effects, and how these CNS effects translate into real-world clinical therapeutic and adverse effects. Following this calibration step, additional patient data were required to evaluate the ability of the QSPainRelief model platform to prospectively predict CNS and clinical effects of treatment combinations in patients. To that end, we conducted a clinical study in patients suffering from disabling post-surgical pain to characterise, using non-invasive biomarkers of CNS activity, the effects of different drug combinations on the CNS networks involved in pain perception and two frequent adverse effects that can be readily explored in patients over a short time interval (sedation and cognitive impairment). Furthermore, we related these effects of drug combinations on CNS activity with the clinical therapeutic and adverse effects self-reported by the patients. These self-reports, collected up to three months after treatment initiation, also included an assessment of pain medication misuse and drug abuse liability. The objectives of WP8 were:

  • To finalise the protocol of the clinical study while taking into consideration the human QSPainRelief models for analgesia and adverse effects developed in WP2
  • To generate a calibration dataset obtained from the first set of patients that will be used to calibrate the QSPainRelief platform (calibration dataset). The preliminary consensus was to include 60 patients in this dataset
  • To generate an evaluation dataset obtained from the second set of patients that will be used to evaluate the QSPainRelief platform (evaluation dataset). The preliminary consensus was to include 120 patients in the evaluation dataset
  • To conduct exploratory analyses linking drug-induced CNS effects to real-life treatment effects (as self-reported by patients)
• WP9 – Dissemination, training and exploitation

  Lead: concentris research management gmbh (concentris)

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  The awareness, acceptance, and knowledge of the burden of chronic pain on the individual patient and its socioeconomic impact are lower compared to other, more obvious diseases. As a consequence, knowledge of the role and potential of effective combinational treatment of chronic pain in individual patients was limited at the beginning of the project and desperately needed improvement. The objectives of WP9 were the development of a communication strategy aimed at outreach to stakeholders in the EU member states, namely academics (clinicians and scientists), patients, caregivers, healthcare providers, regulators, payers, the general public, and patient organisations. A detailed dissemination plan was implemented – in alignment with the following objectives:

  • Make QSPainRelief project known to all stakeholders
  • Disseminate the results to the scientific and medical community, healthcare providers, pharmaceutical and policy sectors, and foster interaction and exchange with the scientific community and patient organisations
  • Identify and valorise the intellectual property rights (IPR) generated within WP2-8
  • Seek European Medicines Agency (EMA) / Federal Drug Associations (FDA) & Health Technology Assessment (HTA) concurrence and feedback on tools that will allow patients stratification and enrichment in future clinical trials and clinical practice for pain in alignment with EMA / Committee for Medicinal Products for Human Use (CHMP) recommendations (incl. guiding documents)
  • Prepare the next generation of scientists in the field of Effective combinational treatment of chronic pain in individual patients
• WP10 – Ethical considerations

  Lead: Alma Mater Studiorum – Università di Bologna (UNIBO)

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  WP10 main objective was to identify and assess the ethical, legal and social issues (ELSI) of the QSPainRelief project and to coordinate the management of the identified ethical issues; thus ensuring that our new discoveries in chronic pain relief research were achieved with utmost adherence to available research ethics guidelines and regulations, and were carried out with the ultimate goal of benefiting society and protecting the interests of research participants. The specific objectives were:

  • To assess the ethical issues and social implications of data collection/management, preclinical and clinical research and bio-banking
  • To provide general ethics support to project partners and to actively monitor ethical and legal issues related to sample and data collection/management and bio-banking throughout the entire project lifetime (and beyond)
  • To provide general ethics support to project partners and to actively monitor ethical and legal issues related to preclinical and clinical research throughout the entire project lifetime (and beyond)