1. Executive summary Year 4 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 final readout for the on-going clinical studies in chronic pain patients, results are delayed but expected to deliver in Year 5. There has also been a delay in some development of the preclinical models, due to unforeseen and project unrelated circumstances. 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 to further characterise signs and symptoms of chronic pain in those patients who develop chronic pain after surgery. Also, the beneficial effect of reoperation for persistent pain after groin hernia surgery in selected patients has been demonstrated. A database of 2000 well characterized patients with chronic neuropathic pain and 1000 healthy controls has been collected. All subjects have undergone a sensory examination and filled in several questionnaires. All sites contributing to the database are quality certified. Analyses of this database are now on-going to improve characterisation of patient symptoms. Better and more reliable quantitative measures and methods to examine patients with neuropathic pain overall, including CRPS, pain due to chemotherapy and persistent pain after surgery have been developed. This data is under publication. Two clinical studies are near completion, investigating if patients with sensitivity to touch and temperature are more prone to respond to treatment with drugs against neuropathic pain. It is estimated one in three patients with neuropathic pain have this characteristic. Improved knowledge may simplify personalized pain treatment. Placebo responses in clinical trials are very unpredictable. A true drug response has been considered to be the difference between placebo and active drug treatment, but our results suggest that the true drug effect is underestimated if the placebo response is large. We are also analysing existing clinical trial data to better understand how placebo responses are affected by how trials are being conducted. Data has been collected and analyses are on-going. A novel brain scan technique for visualizing how the brain reacts to pain, ASL, has been studied and shows good robustness in both healthy individuals and pain patients. Another brain scan technique, RSN, shows characteristic spontaneous brain activity in pain patients. A consensus concerning translation of readouts between pain in animals and humans has been reached and is under publication. A meta-analysis of what are the best ways to assess drug responses in healthy volunteer studies is on-going. Sleep deprivation will increase pain perception in animals as well as in healthy volunteers, mirroring what is seen in pain patients – if they sleep well their pain feels better. Inflammation in skin tissue from healthy volunteers for biomarkers profiling has grown further and has attracted partners also from outside this consortium. Pain from deep tissues is a neglected area of pain research. Deep muscle pain in different models of experimental pain and central sensitization has been investigated and mechanisms are better understood. Validation studies of a highly specialized electrophysiological technique, microneurography, as a measure of on-going pain is underway, and is shown to be valid for measurements in animals and in humans. With regard to pain comorbidities, we have found a parallel to pain patients with regard to impairment of sleep and cognition / attention. A new and more disease relevant animal model of diabetes polyneuropathy has been developed and validated. The human pain model of local administration of NGF and UVB irradiation has been translated to animals. The experimental protocol library is initiated. Validation of burrowing and thigmotaxis as new outcome measures of spontaneous pain behaviour in rodents has been further refined. Social discrimination deficit in rats is a new measure of cognitive deficit caused by chronic pain. Replication studies of this measure are now underway. The final tune for Next Generation Sequences (NGS), lipidomics and proteomics analysis of several pain relevant tissues is under completion. We have identified new mechanisms of brain adaptation in neuropathic pain. We have also identified a new mediator in inflammatory pain, LPA 18:0. A web database called “pain Networks” has been finalized, enabling global sharing and integrating of pain related genetic data. 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.