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 intraproject 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 1
Description 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 intrathoracic 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