Europain Yearly Report Year 1, Publishable Summary

1.Publishable summary

Europain yearly report year 1, Publishable summary

The project addresses the current lack of better and safer treatment for pain. The ultimate goals of the project are to increase the understanding of chronic pain mechanisms in order to improve the development of pharmacological treatment against pain. In the end, the project is hoping to reduce the burden of illness of very large groups of the European population.

The established team of leading researchers and clinicians from both academia and industry has undertaken a multidisciplinary translational research including a series of six interlinked and mutually supportive programs of experimental research, underpinned and supported by a coordinated training and bioinformatics facility.

Two of the research programs has study pain in preclinical models (with the major aims of identifying novel biomarkers and other pain mediators; elucidating different nervous system changes contributing to pain; refining animal models of pain and measurement of pain in these models). Three programs explore human pain mechanisms (aiming at establishing and validating mechanism-based pain models in volunteers; finding objective measures of spontaneous pain; detailed characterisation of clinical findings in chronic pain patients; and determining psychosocial and clinical risk factors for development of chronic pain). One program is integrating data via a common data warehouse. This will be a source for intra-project data mining. The whole program is divided into a series of interlinked work packages (WPs), the contents of which are detailed and illustrated in the below figure.

Figure 1Description of Work Packages

The first year of this unique 5-year partnership of members of the European Federation of Pharmaceutical Industries and Associations (EFPIA), and academic centres of excellence and one small and medium enterprise (SMEs) has been very fruitful, with the following tasks already delivered or in process.

In all, the expected final results will have identified risk factors for developing chronic pain and clarified the underlying mechanisms, including psychosocial and genetic factors, as well as biomarkers involved in initiation and maintenance of chronic pain. To be able to develop better treatments for chronic pain mechanisms need to be clarified and possible to identify at a doctor’s office. Therefore, simple standardised examination techniques are being used to identify signs and symptoms specific for different pain generating mechanisms. Typical response patterns to well-known drugs as well as factors influencing the placebo response are being investigated to find ways of designing better trials for the development of new and better analgesics to treat chronic pain. Using better and more relevant methods, animal models will be better to predict analgesic effects in humans. Biochemical methods will have identified new drug targets for pain treatment. In all, the result of this joint Academia and Pharma project will improve the possibility of success in the development of new analgesics for the benefit of individual patients and the health of the general population.

Risk factors for and prevention of chronic pain

Results from a thorough literature review concluded that studies investigating chronic pain after treatment for breast cancer use very differing methodologies and endpoint and therefore are difficult to compare. This prompts risk factors to be investigated in a more systematic way, including as many possible factors as possible, to be able to develop a prevention strategy. In the Post Thoracotomy Pain Syndrome, risk factors for chronic pain after intra-thoracic surgery have been studied in a nationwide study serving as a rational basis for future prospective studies. One major conclusion is that PTSP is relatively common, 12-18% of patients experience continuous moderate to severe pain 2 years after surgery, and seriously impairs the daily life of these patients. In PTPS more detailed clinical examinations have been performed and have identified that symptoms of sensory skin disturbances are common among patients with and without pain, but hypersensitivity to touch or temperature are more comprehensive in patients with pain.

The patient suffering chronic neuropathic pain

Chronic neuropathic pain is characterized by the presence of both spontaneous ongoing pain and different types of evoked pain. In this work package a series of different measures is being used in patients suffering different neuropathic pain of different origins in order to determine generators/mechanisms for pain and compare it to perceived/experienced ongoing and evoked pain.

The consortium has developed a database based on the standardized DNFS QST protocol to identify potential underlying mechanisms. In the EuroPain database a number of patient reported assessment instruments would be used, the partners decided on 8 validated questionnaires. All necessary licensing and translation of these has been established to progress the project. The establishment of a functioning database is the first milestone of the EuroPain project and was completed successfully.

A novel imaging technique, Resting Brain Activity (RSN) based on Magnetic Resonance Imaging technique (MRI), has been able to visualise changes in how the normal brain resting state network is altered in chronic low-back pain patients vs. healthy controls. We could also show that repeated exposure to pain induces changes in the resting brain neural networks and can anticipate the individual level of habituation to perception and allows prediction of pain intensity ratings.

The aim of EuroPain is to validate RSN methodology in male and female patients with chronic pain of different origin (osteoarthritis, painful diabetic neuropathy, visceral pain and wide-spread pain. This will allow us to delineate a disease specific or generalized modification of resting activity in chronic pain populations. In addition to measurements of ongoing pain, the response to increased pain will be assessed. Results will help us understand if there is a difference in how our brains perceive pain based on origin and type of pain, gender or previous individual pain experiences.

Translational pain models in humans

It is well known that patients with neuropathic pain have vary variable changes in sensory perception of eg, touch and temperature, irrespective and independent of underlying painful disease. These discrepancies are thought to be due to differences in underlying mechanisms of symptom generation, and are thought to be one major reason behind the low percentage of responders to any single medication. Experimental pain models in healthy humans can selectively activate specific disease related mechanisms (eg, peripheral and/or central sensitization, ectopic activity) and could bridge the gap between animals and patients by using methodology from both ends. Progress in the first year includes completion of the sensory profiling of a new model for cold hypersensitivity, revealing similarity to chemotherapy induced pain, neurophysiological investigations in neuropathic pain patients, and preparatory work for three additional human pain models, gene expression profiling in rat and humans after UVB induced inflammation.

Improving animal models of pain

As most early steps in analgesic drug development is based on animal models, it is a challenge to develop models that both are relevant models of pain. The challenge in translating pain behaviour into human pain, and to reflect the same disease mechanisms that lie behind clinical pain states is being addressed. The work package aims to deliver three new models of neuropathic pain during the first 3 years, as a means to develop new medicines. Development of new animal models for painful diabetic neuropathy and neuropathic pains, induced by antiretroviral treatment and chemotherapy, has been initiated and results are expected in the third year of the project.

At present, measurements of pain in animal models are based on the reaction to different noxious stimuli. The work package is exploring new outcome measures to reflect pain related behaviours such as social interaction tests and other spontaneous behaviours as signs of spontaneous pain. During the first year, work has focused on anxiety and spontaneous pain measures. Current focus is on social interaction tests for measuring anxiety in pain models and on place preference and burrowing as measures of spontaneous pain. Sleep EEG changes in naive rats following gabapentin have been measured. Well characterised pain models will be used to develop these new drug efficacy measurements. A novelty discrimination index for cognitive function has also been established and deficits were observed in the reference tibial nerve transection model of neuropathic pain, which were reversed by gabapentin. The results have been discussed and the best way forward has been agreed during the first project internal scientific conference.

Standardisation and best practise is essential in doing this laboratory work, to ensure ethics and quality. A library for used models is being put together. The first protocol for the library has been being peer-reviewed and there will be a consensus meeting later on in the project.

Neurobiological mechanism of chronic pain

Established inflammatory markers have been detected in skin from humans and animals, and are found to inter-correlate. This is an important basis for coming steps in developing an understanding of what established models of inflammation represent.

Zymosan-induced inflammation causes a marked thermal and mechanical hyperalgesia in mouse tissue that is the result of inflammatory mediators acting at the site of injury. Here we have determined levels for over 87 different lipid mediators in inflamed versus control tissues in adult mice. Levels were measured to monitor lipid levels during onset, maintenance and resolution of inflammation. For some of the putative lipid mediators, the inflammation caused a more than 30-fold increase in levels. These may become new targets for analgesic drug development.

Creating a common results database

There are already well established databases within the consortium, LPD (London Pain Consortium) and QUAST (DFNS Germany), capturing different aspects of chronic pain, both genotypic and phenotypic. These databases will include study results from ingoing studies in order to be able to fully utilise the potential of the wealth of information collected in this large consortium. Such information will give the future possibility to tailor pain treatments based on sensory examination results, combined with genetic predisposition. All data in the database is stored in anonymised form, without any possibility to identify any individual data