New guidance published by Europain aims to help other pain researchers comply with EU regulations.

Workpackage 2 of the Europain collaboration is focused on improving animal models of pain.
The team of academic and industry researchers has reviewed their work in the context of the EU Directive 2010/63/EU (on the protection of animals used for scientific purposes) and provided guidance to other pain researchers on the required classification of severity of experiments.
Speaking about the new guidance, Europain Work Package 2 leader Ian Machin said “We are pleased to share guidance based on our experience to help other preclinical researchers to comply with an EU directive which has been rolling out over the last 3 years”.
Please follow this link to read a copy of the guidance and find out about the conclusions.



Understanding chronic pain and improving its treatment – IMI EUROPAIN


Executive Summary year 5


1.1 Project rationale and overall objectives of the project

Chronic pain affects one in five European citizens and is one of the major burdens of society, both from an individual suffering perspective as well as a socioeconomic burden for society. With current treatments, only one third of patients obtain adequate pain relief. The EUROPAIN consortium aims at better understanding of the mechanisms of chronic pain, thereby contributing the development of better and more efficacious treatment options for this large group of patients by addressing the bottlenecks in drug development. In the end, the project is hoping to reduce the burden of illness of large groups of the European population.


1.2 Overall deliverables of the project

This established team of leading researchers and clinicians from the 22 private, public and SME partners has undertaken an integrated and multidisciplinary translational approach in addressing the overall objective. The members of the consortium have organized themselves into 8 distinct but closely interlinked, mutually supportive and closely collaborating work packages, six of them conducting experimental research, and two focusing on coordinated training, bioinformatics and project management in order to efficiently address the overall project objective. Thus, the overall objective to overcome the bottlenecks of the development of new analgesics is being addressed from several perspectives, where deliverables aim at improving: (1) Translational biomarkers; (2) Predictability of efficacy from animal to human volunteer surrogate models to patients; (3) Relevant translational models to study pain co-morbidities; (4) Patient stratification making it more relevant to patient complaints and phenotypes; (5) Knowledge of predictive factors for development of neuropathic pain; (6) Operational excellence in preclinical studies; (7) Operational excellence clinical study design and conduct with regard to clinical investigator training and placebo response prediction.


1.3 Summary of progress versus plan since last period


There have been no major deviations from the current description of work affecting overall project objectives or deliverables. However, there have been some delays and mitigation plans are into place where needed. For the remaining on-going clinical studies in chronic pain patients, all data is collected and under analysis. For the previously delayed development of the preclinical models, mitigation plan have been successful and data collection has been completed, and analyses are ongoing. The protocol library is awaiting completion after the aforementioned data analysis. Consensus guideline publications have been resubmitted and is in manuscript phase, respectively. Meta-analysis of preclinical and human experimental data is underway. The meeting with eTriks to clarify how the platform enabling that the clinical database can be made available after end of project has been delayed due to technical and time constraints on behalf of eTriks. The preparations for the regulatory scientific biomarker advice have been delayed but are now underway.


1.4 Significant achievements since last report

This last year several studies in chronic pain after groin hernia repair, breast cancer surgery and thoracic surgery have been published or submitted for publication, further characterizing signs and symptoms of chronic pain in those patients who develop chronic pain after surgery. This includes predictive factors, validation of diagnosis specific tools for functional assessment as well as the impact of different surgical techniques and type of chemotherapy used on the incidence of chronic pain after surgery and adjunctive cancer treatment.
The clinical database of 2000 well characterized patients with chronic neuropathic pain and 1000 healthy controls has been further data-mined and a number of publications have been published or are underway. A close collaboration with the Neuropain clinical consortium has developed further including a common publication strategy. The clinical study investigating if patients with sensitivity to touch and temperature are more prone to respond to treatment with drugs against neuropathic pain was positive, supporting the hypothesis. Results are published in Pain. A post hoc analysis identified risk factors for placebo response and for treatment response. The second study testing the same hypothesis is under analysis. These results will, together with data showing the paramount importance of peripheral contribution, constitute part of the basis for the EMA biomarker qualification advice for patient stratification. Improved knowledge may serve as a patient stratification tool in clinical development programs and to simplify personalized pain treatment.
The placebo response meta-analysis demonstrated that type of drug was the only factor significantly influencing the placebo response, opioid trials having a greater placebo response. Further studies on placebo and nocebo point to the importance of controlling for these effects in clinical trials in volunteers and in patients.
Results from an imaging study in healthy volunteers subjected to capsaicin injection and analgesics give sample size estimates for imaging endpoints useful in small proof of concept studies for drug development.
Neuronal mechanism behind the increased pain sensitivity from sleep deprivation on pain has been investigated further, in rats and human volunteers in parallel and central pain modulatory mechanisms are involved in parallel to negative cognitive effects. Studies on inflammation in skin tissue from healthy volunteers for biomarkers profiling has expanded further and has attracted partners also from outside this consortium. Lipidomics are now also done in the UVB model to further strengthen the translational link. However, UVB irradiation does not give rise to spontaneous activity in pain fibers of C-type, while this is the case after topical application of capsaicin. A highly specialized electrophysiological technique, microneurography, has been shown to be valid for measurements in animals and in human volunteers and patients. A protocol for pharmacological validation in neuropathic pain patients is ongoing as a last step to validate invasive and non-invasive C-fiber recordings as a valid translational tool.
A new and more disease relevant animal model of diabetes polyneuropathy, the ZDF model, has now been further validated and compared to other models of diabetes polyneuropathy. Microneurography has been successfully performed and will now be directly compared to data from patients with painful diabetic polyneuropathy. From a pathophysiological perspective it is clearly superior to current standard models. The antiviral polyneuropathy rat model is now also histologically validated. The burrowing data from all labs has been pooled and preliminary meta-analysis data shows that the same pain model induced a consistent burrowing deficit at all participating labs as well as consistent response to treatment. The data is promising for this measure of spontaneous pain behavior and further analyses are ongoing. The social discrimination deficit and elevated maze models are validated in a model of spinal cord injury. A guidance document on how to comply with a new EU directive on animal studies in pain has been published on the project website.
The transgenic “knock-in” mouse strain of the NaV-channel SCN9a loci (K1449V and L858F mutations) show the expected phenotype of spontaneous pain related behaviour.
Overall, there has been extensive collaboration between partners and between work packages, ensuring an optimised joint effort in solving the project overall aims of reducing hurdles for developing new treatment options for chronic pain.






Executive Summary year 4. Please follow this link to read the year 4 Executive Summary.


Executive Summary year 3. Please follow this link to read the year 3 Executive Summary.


Publishable Summary year 2. Please follow this link to read the year 2 Publishable Summary.


Publishable Summary year 1. Please follow this link to read the year 1 Publishable Summary.