REPORTS
Pain research funding by the European Union Seventh Framework Programme Accepted for publication 28 January 2015 doi:10.1002/ejp.690
It is well known to the regular readers of this Journal that chronic pain is a major health care problem as defined by the World Health Organization. A recent literature review showed a 1-month prevalence of moderate to severe non-cancer pain in European adults of 19% and of subjects older than 70 years even one in three is affected (Elliott et al., 1999; Breivik et al., 2006). With an EU population of half of a billion in 2010, this impacts on 80 million Europeans suffering from chronic pain (http:// euobserver.com/social/30551) and projects with high socio-economic costs due to medical expenses and lost working days (Hill and Schug, 2009; Reid et al., 2011). The high prevalence of chronic pain clearly points at insufficient treatment options. Indeed, evidence from Cochrane systematic reviews shows that the available analgesic drugs provide efficacious pain relief, defined as a decrease in the intensity of pain by 50% lasting for 12 weeks, only in a minority of patients (Moore et al., 2009, 2012; Derry et al., 2012). Hence, analgesics with novel mechanisms of action are required that need to be developed on the basis of a better understanding of the complex pathophysiology (Julius and Basbaum, 2001) and clinical representation of pain. It is increasingly recognized that pain is not a mere symptom which disappears together with the causing condition, hence the often perceived under-representation of pain in the financial volume of earlier funding directs investments towards the underlying diseases, but pain is a disease that requires specific treatment. Among typical examples, the post-zoster neuropathic pain that may persist long after the acute virus-caused inflammation has been resolved and that would not benefit from continued antiinfective therapy, but clearly requires specific pain treatment. Similarly, the treatment of migraine requires specific therapeutics and cannot be addressed by solving some underlying disease as the pain condition itself is the disease. Moreover, neuro-
© 2015 European Pain Federation - EFICâ
pathic phantom pain clearly requires analgesic treatment considering the evident lack of alternative options to repair its reason. This is reflected in the present funding policy of the European Union that in its currently active Seventh Framework Programme (FP7) supports pain research with a total of more than 46 million Euros provided to eight groups (Table 1) of collaborating clinical and basic scientists at locations spanning almost the whole geographical extension of our home continent (Fig. 1 and Table 2). The funding policy accommodates (1) the increasing awareness of the importance of the treatment of pain as a human right (International Covenant on Economic, Social and Cultural Rights, 1966) and (2) the recognition of chronic pain conditions as diseases rather than symptoms of another disease. Understanding the pathophysiological mechanisms of pain is the logical scientific path to effective and safe novel personalized therapy options. After the first year of the funding, all projects have been established and can be acknowledged in the official journal of the European Pain Federation EFICâ where many European pain scientists are united via national societies. One research focus of the funded projects comprises chronic pain conditions, e.g. low back pain, migraine or neuropathic pain. Most projects combine preclinical with clinical research in both, a translational concept or its opposite, i.e. in a bedside-to-bench direction that obtains its principal information from human data and uses laboratory experiments not to generate new hypotheses but to verify those obtained by clinical observation (L€ otsch and Geisslinger, 2010). The eight projects (Table 1 and Fig. 1) will be summarized in the following paragraph in the succession of their appearance at the FP7 website at http://ec.europa. eu/research/health/medical-research/brain-research/l_ coor_en.htm and based on the websites of single projects or personal communications from project speakers.
Eur J Pain 19 (2015) 595--600
595
EU FP7 pain funding
(A) Chronic low back pain, described as a discomfort condition in the local region around the posterior ribs and upper pelvis, affects an estimated 15–45% of the population at some point in life (Andersson et al., 1993; Van Tulder et al., 1995) and may become persistent when symptoms endure longer than 6 weeks and as ‘chronic’ when pain persists beyond 12 weeks (Krismer, 2007). The PAIN-OMICS project aims at the stratification of patients with low back pain. This multidisciplinary consortium will use a complex systems biology approach at the understanding of low back pain in a high-dimensional data set from more than 5000 patients. This project aims at prospectively establishing new genomic, epigenetic and glycomic (i.e. study of all glycan structures from a cell type or an organism) approaches to identify novel diagnostic and prognostic biomarkers and new therapeutic targets that could predict the risk that acute low back pain becomes chronic. (B) Migraine, typically characterized by recurrent moderate to severe headaches, autonomic dysfunction and sometimes aura symptoms, affects an estimated 15% of the population at some point in their life (Stovner et al., 2007). Currently, approved medications are only moderately effective and the particular need of effective prophylactic treatments to prevent attacks and chronification is poorly met. This owes to the incomplete understanding of the trigger mechanism of migraine attacks and of the reasons why in some patients their frequency increases. To narrow this gap of knowledge, the EUROHEADPAIN approaches the pathomechanisms and treatment options of migraine and its chronification by employing established and evolving human and preclinical research models to identify pathways and biomarkers of migraine attacks and to decipher the modulatory effects of brain circuitries on trigeminal processing, sensitization and chronification. (C) Neuropathic pain develops as a result of lesions or disease affecting the somatosensory nervous system either in the periphery or centrally (Baron et al., 2010). Up to 8% of the European population is affected and has often a great impact on their quality of life (Torrance et al., 2006). Disease or anatomy-based classifications of neuropathic pain comprise painful focal, multifocal or generalized peripheral neuropathies, central pain syndromes, complex painful neuropathic disorders and mixed pain syndromes (Baron et al., 2010). Neuropathic pain is considered to be one of the greatest challenge for pain research and therapy, as current treatment options are sparse mainly consisting of a combination of opioids and re-purposed antidepressants and 596 Eur J Pain 19 (2015) 595--600
€tsch D. Kringel, J. Lo
anti-epileptics that reduce the pain yet, but neither abolish it in most patients, nor prevent its evolvement towards chronification following nerve injury. The complexity of neuropathic pain is reflected in the funded projects that pursue several approaches comprising the development of sensory feedback tools for phantom limb modulation, the study of neuroinflammation and glial activation, of non-coding ribonucleic acids, sodium channels or the nerve growth factor, or the cross-validation of innovative chronic pain models and biomarkers in preclinical and clinical settings. One peripheral form is phantom limb pain, which often develops in association with the phantom limb syndrome, i.e. a perception of sensations in the amputated limb (Ramachandran and Hirstein, 1998), in about 60–80% of amputees (Sherman et al., 1984). Recent evidence suggests that phantom limb pain may be related to changes in neuronal plasticity in the cerebral cortex, which can be modulated by sensory input to the amputation zone (McCormick et al., 2014). This is intended to be exploited by the EPIONE consortium for developing a natural sensory feedback for phantom limb modulation and therapy. The project aims at offering technological solutions that will invasively or non-invasively induce natural, significant sensations to the amputee to restore the neuroplastic changes in the cortex and thereby control and alleviate phantom limb pain. The consortium will build solutions based on existing technologies, but presently only available in experimental settings. (D) The main hypothesis pursued by the GLORIA project is that neuroinflammation and glial activation play an important role in neuropathic pain and other chronic pain conditions and are involved in opioidinduced adverse effects such as tolerance. The project combines basic and clinical research, assesses markers of inflammation and glial activation in the cerebrospinal fluid and the brain (PET), and employs experimental pain models, genetic and epigenetic analyses. It aims at identifying complex high-dimensional phenotypes in more than 1000 pain patients as a basis to explain the symptoms and analgesic responses and to develop a biomarker profile for clinical conditions. This will be used to engineer new molecules providing novel analgesics with a better efficacy and safety profile than the therapeutic agents which are currently available. (E) Non-coding ribonucleic acids (ncRNAs) comprise a heterogeneous group from short- to mediumlength RNA molecules among which several members play important roles in the regulation of © 2015 European Pain Federation - EFICâ
€tsch D. Kringel, J. Lo
EU FP7 pain funding
Table 1 Pain-related projects that receive support from the European Union within its Seventh Framework Programme (FP7/2007–2013). The list has been taken from the official site of this programme at http://ec.europa.eu/research/health/medical-research/brain-research/l_coor_en.htm where further details including speaker’s names and addresses can be obtained, if not from the web representations of the single project showed in this table. The succession of projects corresponds with their appearance in that original document. Project title (A) PAIN-OMICS: Multidimensional omics approach to stratification of patients with low back pain (B) EUROHEADPAIN: Mechanisms and treatment of migraine and its chronification (C) EPIONE: Natural sensory feedback for phantom limb pain modulation and therapy (D) GLORIA: Understanding chronic pain and new druggable targets: Focus on glial–opioid receptor interface (E) NCRNAPAIN: Non-coding RNAs in neurogenic and neuropathic pain mechanisms and their application for risk assessment, patient stratification and personalized pain medicine (F) PROPANE STUDY: Probing the role of sodium channels in painful neuropathies (G) PAINCAGE: The NGF system and its interplay with endocannabinoid signalling, from peripheral sensory terminals to the brain: new targets for the development of next generation drugs for neuropathic pain (H) NEUROPAIN: Neuropathic pain: Biomarkers and druggable targets within the endogenous analgesia system
Project coordinator
Kind of chronic pain
Website
Massimo Allegri
Low back pain
http://www.painomics.eu
Michel Ferrari
Migraine
http://www.euroheadpain.org
Winnie Jensen
Neuropathic (phantom limb pain)
http://project-epione.eu
Eija Kalso
Neuropathic and other
http://gloria.helsinki.fi
Michaela Kress
Neuropathic
http://www.ncrna-pain.eu
Giuseppe Lauria
Neuropathic
http://www.propanestudy.eu
Antonino Cattaneo
Neuropathic
http://www.paincage.eu/
Rafael Maldonado
Neuropathic
http://www.upf.edu/neuropain
gene expression including those involved in immune and neuronal processes (Bartel, 2009; Ghildiyal and Zamore, 2009). Therefore, ncRNAs may act as critically important master switches for chronic pain, which the NCRNAPAIN consortium intends to exploit for risk assessment, patient stratification and personalized therapy approaches. The project aims at decoding these biological molecules’ role towards a better understanding of ncRNA regulation of nociception and endogenous analgesia and to identify and validate ncRNAs as molecular targets for pain prevention and pain relief. (F) Voltage-gated sodium channels play a key role in the transmission of nociceptive information and thus, for pain perception and chronification (DibHajj et al., 2010). The PROPANE project aims at resolving the genetic architecture of idiopathic and diabetic painful neuropathies through a complementary approach based on targeted sequencing of the five sodium channel genes expressed in the nociceptive pathway and identification of new targets by © 2015 European Pain Federation - EFICâ
unbiased whole exome sequencing and transcriptome assay. Its main objectives include to achieve a stratification of patients with high-risk to develop neuropathic pain by the discovery of novel biomarkers and to identify novel molecular targets for drug development. (G) The nerve growth factor (NGF) is a neurotrophin, which is critical for development and survival of neuronal cells (Barde, 1990). Variants in the nerve growth factor gene (NGFB) have been associated with a loss of pain perception (Hilz, 2002) suggesting its potential suitability as a novel drug target for the treatment of neuropathic pain, which is supported by the additional involvement of NGF in the modulation of endocannabinoid signalling known as a further player in neuropathic pain (Keimpema et al., 2013). At this point enters the research of the PAINCAGE consortium whose members aim at investigating strategies for the treatment of neuropathic pain based on the NGF system and its interplay with endocannabinoid signalling. The project addresses mechanistic Eur J Pain 19 (2015) 595--600
597
EU FP7 pain funding
€tsch D. Kringel, J. Lo
Figure 1 Geographic map of Europe showing the locations of the active pain research projects that receive active funding within the European Union Seventh Framework Programme (FP7/2007–2013). The locations are shown as spots coloured according to the eight consortia where the specific project belongs. The central part of Europe has been magnified for better visibility of the map. Not shown are collaborators outside the continent, i.e. in Indianapolis (EPIONE), Boston (EUROHEADPAIN) and New Haven (PROPANE), United States, and Brisbane (EUROHEADPAIN), Australia. The map was created using the libraries ‘ggmap’ (http://cran.r-project.org/web/packages/ggmap/index.html) and ‘car’ (http://cran.r-project.org/ web/packages/car/index.html) in R (version 3.0.2 for Linux; http://CRAN.R-project.org/). The underlying map was imported as the ‘Europe’ Map from Google Map Data ©2014, Basarsoft, Google Imagery ©2014 terra metric, 6 Dec. 2014.
bases for the development of already identified second-generation therapeutics, new molecular targets for drug development and biomarkers. (H) A major handicap for the finding of effective cures for neuropathic pain is the poor predictive 598 Eur J Pain 19 (2015) 595--600
validity of currently available preclinical chronic pain models (Mogil, 2009) that do not simulate the multidimensional and highly variable (Maier et al., 2010) clinical phenotype. The NEUROPAIN consortium therefore focuses on the validation of new preclinical © 2015 European Pain Federation - EFICâ
€tsch D. Kringel, J. Lo
EU FP7 pain funding
Table 2 Detailed localizations of the table with the research groups involved in the pain-related projects that receive support from the European Union within its Seventh Framework Programme (FP7/2007–2013). See also Table 1 and Fig. 1 for further details. Project title
Participant Country/City
Project title
Participant Country/City
(A) PAIN-OMICS
Italy/Parma Belgium/Genk Croatia/Zagreb Italy/Pavia United Kingdom/London Germany/Munic Netherlands/Rotterdam Croatia/Zagreb France/Noisy Le Grand United States/Winston-Salem Australia/Joondalup Netherland/Leiden ge Belgium/Lie Germany/Hamburg Finnland/Helsinki Australia/Brisbane Italy/Trieste Germany/Erlangen Denmark/Copenhagen United Kingdom/London Denmark/Aalborg Italy/Rome Switzerland/Lausanne United States/Indianapolis Sweden/Lund France/Montpellier France/Nice Germany/Freiburg Spain/Barcelona Finland/Helsinki Sweden/Stockholm Germany/Frankfurt Sweden/Lund Estland/Tartu
(E) NCRNAPAIN
Austria/Innsbruck Germany/Heidelberg €rzburg Germany/Wu Germany/Mainz €cken Germany/Saarbru United Kingdom/London France/Bordeaux Czech Republic/Brno Italy/Rome Denmark/Kopenhagen Israel/Jerusalem Italy/Milano Netherlands/Maastricht United States/New Haven United Kingdom/Manchester Germany/Berlin France/Paris
(B) EUROHEADPAIN
(C) EPIONE
(D) GLORIA
models to evaluate the electrophysiological, behavioural, emotional and cognitive manifestations of neuropathic pain and the effectiveness of novel analgesic compounds, with special attention on biomarkers and molecular targets for drug development within the endogenous analgesia system. In concert with clinical studies and genetic approaches, a translational focus will be set based on cross-validation of the findings in preclinical and human observations. Current EU funding supports preclinical and clinical studies of chronic pain in its various clinical facets, of which the most prevalent conditions will be analysed with respect to biomarkers, genetics and epigenetics, functional magnet imaging and other contemporary methods and readouts. This comprehensible clinical © 2015 European Pain Federation - EFICâ
(F) PROPANE STUDY
(G) PAINCAGE
(H) NEUROPAIN
Italy/Rome Denmark/Aarhus Austria/Vienna United Kingdom/Sandwich United Kingdom/London Spain/Salamanca Italy/Milano Italy/Pisa France/Paris Spain/Barcelona United Kingdom/London United Kingdom/Salisbury France/Illkirch Germany/Bonn Germany/Berlin Poland/Cracow Iceland/Reykjavik Finland/Helsinki
neuroscience of pain will be accompanied with preclinical assessments using the contemporary repertoire of bio-medical and bio-informatics and computer science methods. Owing to the funding and the expertise gathered in the consortia, in the next several years the results will begin to emerge. Acknowledgements This paper was written using Free Software programs on office and portable PCs running GNU/Linux. This communication is a contribution of the GLORIA consortium funded by the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 602919 (JL). The authors are beneficiaries of this funding.
Eur J Pain 19 (2015) 595--600
599
€tsch D. Kringel, J. Lo
EU FP7 pain funding
The authors have declared that no further conflicts of interest exist.
Dario Kringel, J€ orn L€ otsch Institute of Clinical Pharmacology, Goethe – University, Frankfurt am Main, Germany Correspondence J€ orn L€ otsch Email: [email protected] Funding sources This communication is a contribution of the GLORIA consortium funded by the European Union Seventh Framework Programme (FP7/2007 – 2013) under grant agreement no. 602919 (JL). The authors are beneficiaries of this funding. Conflicts of interest None declared.
References Andersson, H.I., Ejlertsson, G., Leden, I., Rosenberg, C. (1993). Chronic pain in a geographically defined general population: Studies of differences in age, gender, social class, and pain localization. Clin J Pain 9, 174–182. Barde, Y.A. (1990). The nerve growth factor family. Prog Growth Factor Res 2, 237–248. Baron, R., Binder, A., Wasner, G. (2010). Neuropathic pain: Diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol 9, 807–819. Bartel, D.P. (2009). MicroRNAs: Target recognition and regulatory functions. Cell 136, 215–233. Breivik, H., Collett, B., Ventafridda, V., Cohen, R., Gallacher, D. (2006). Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. Eur J Pain 10, 287–333. Derry, S., Gill, D., Phillips, T., Moore, R.A. (2012). Milnacipran for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 3, CD008244. Dib-Hajj, S.D., Cummins, T.R., Black, J.A., Waxman, S.G. (2010). Sodium channels in normal and pathological pain. Annu Rev Neurosci 33, 325–347. Elliott, A.M., Smith, B.H., Penny, K.I., Smith, W.C., Chambers, W.A. (1999). The epidemiology of chronic pain in the community. Lancet 354, 1248–1252. Ghildiyal, M., Zamore, P.D. (2009). Small silencing RNAs: An expanding universe. Nat Rev Genet 10, 94–108.
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Hill, L., Schug, S.A. (2009). Recent advances in the pharmaceutical management of pain. Expert Rev Clin Pharmacol 2, 543–557. Hilz, M.J. (2002). Assessment and evaluation of hereditary sensory and autonomic neuropathies with autonomic and neurophysiological examinations. Clin Auton Res 12(Suppl 1), I33–I43. Julius, D., Basbaum, A.I. (2001). Molecular mechanisms of nociception. Nature 413, 203–210. Keimpema, E., Tortoriello, G., Alpar, A., Capsoni, S., Arisi, I., Calvigioni, D., Hu, S.S., Cattaneo, A., Doherty, P., Mackie, K., Harkany, T. (2013). Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons. Proc Natl Acad Sci USA 110, 1935– 1940. Krismer, M. (2007). Low back pain (non-specific). Best Pract Res Clin Rheumatol 21, 77–91. L€ otsch, J., Geisslinger, G. (2010). Bedside-to-bench pharmacology: A complementary concept to translational pharmacology. Clin Pharmacol Ther 87, 647–649. Maier, C., Baron, R., T€ olle, T.R., Binder, A., Birbaumer, N., Birklein, F., Gierthm€ uhlen, J., Flor, H., Geber, C., Huge, V., Klug, R., ofner, C., Rolko, C., Schaub, Landwehrmeyer, G.B., Magerl, W., Maih€ C., Scherens, A., Sprenger, T., Valet, M., Wasserka, B. (2010). Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain 150, 439–450. McCormick, Z., Chang-Chien, G., Marshall, B., Huang, M., Harden, R.N. (2014). Phantom limb pain: A systematic neuroanatomicalbased review of pharmacologic treatment. Pain Med 15, 292–305. Mogil, J.S. (2009). Animal models of pain: Progress and challenges. Nat Rev Neurosci 10, 283–294. Moore, R.A., Straube, S., Wiffen, P.J., Derry, S., McQuay, H.J. (2009). Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev 3, CD007076. Moore, R.A., Derry, S., Aldington, D., Cole, P., Wiffen, P.J. (2012). Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 12, CD008242. Ramachandran, V.S., Hirstein, W. (1998). The perception of phantom limbs. The D. O. Hebb lecture. Brain 121(Pt 9), 1603–1630. Reid, K.J., Harker, J., Bala, M.M., Truyers, C., Kellen, E., Bekkering, G.E., Kleijnen, J. (2011). Epidemiology of chronic non-cancer pain in Europe: Narrative review of prevalence, pain treatments and pain impact. Curr Med Res Opin 27, 449–462. Sherman, R.A., Sherman, C.J., Parker, L. (1984). Chronic phantom and stump pain among American veterans: Results of a survey. Pain 18, 83–95. Stovner, L., Hagen, K., Jensen, R., Katsarava, Z., Lipton, R., Scher, A., Steiner, T., Zwart, J.A. (2007). The global burden of headache: A documentation of headache prevalence and disability worldwide. Cephalalgia 27, 193–210. Torrance, N., Smith, B.H., Bennett, M.I., Lee, A.J. (2006). The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain 7, 281–289. Van Tulder, M.W., Koes, B.W., Bouter, L.M. (1995). A cost-of-illness study of back pain in The Netherlands. Pain 62, 233–240.
© 2015 European Pain Federation - EFICâ
Pain research funding by the European Union Seventh Framework Programme Accepted for publication 28 January 2015 doi:10.1002/ejp.690
It is well known to the regular readers of this Journal that chronic pain is a major health care problem as defined by the World Health Organization. A recent literature review showed a 1-month prevalence of moderate to severe non-cancer pain in European adults of 19% and of subjects older than 70 years even one in three is affected (Elliott et al., 1999; Breivik et al., 2006). With an EU population of half of a billion in 2010, this impacts on 80 million Europeans suffering from chronic pain (http:// euobserver.com/social/30551) and projects with high socio-economic costs due to medical expenses and lost working days (Hill and Schug, 2009; Reid et al., 2011). The high prevalence of chronic pain clearly points at insufficient treatment options. Indeed, evidence from Cochrane systematic reviews shows that the available analgesic drugs provide efficacious pain relief, defined as a decrease in the intensity of pain by 50% lasting for 12 weeks, only in a minority of patients (Moore et al., 2009, 2012; Derry et al., 2012). Hence, analgesics with novel mechanisms of action are required that need to be developed on the basis of a better understanding of the complex pathophysiology (Julius and Basbaum, 2001) and clinical representation of pain. It is increasingly recognized that pain is not a mere symptom which disappears together with the causing condition, hence the often perceived under-representation of pain in the financial volume of earlier funding directs investments towards the underlying diseases, but pain is a disease that requires specific treatment. Among typical examples, the post-zoster neuropathic pain that may persist long after the acute virus-caused inflammation has been resolved and that would not benefit from continued antiinfective therapy, but clearly requires specific pain treatment. Similarly, the treatment of migraine requires specific therapeutics and cannot be addressed by solving some underlying disease as the pain condition itself is the disease. Moreover, neuro-
© 2015 European Pain Federation - EFICâ
pathic phantom pain clearly requires analgesic treatment considering the evident lack of alternative options to repair its reason. This is reflected in the present funding policy of the European Union that in its currently active Seventh Framework Programme (FP7) supports pain research with a total of more than 46 million Euros provided to eight groups (Table 1) of collaborating clinical and basic scientists at locations spanning almost the whole geographical extension of our home continent (Fig. 1 and Table 2). The funding policy accommodates (1) the increasing awareness of the importance of the treatment of pain as a human right (International Covenant on Economic, Social and Cultural Rights, 1966) and (2) the recognition of chronic pain conditions as diseases rather than symptoms of another disease. Understanding the pathophysiological mechanisms of pain is the logical scientific path to effective and safe novel personalized therapy options. After the first year of the funding, all projects have been established and can be acknowledged in the official journal of the European Pain Federation EFICâ where many European pain scientists are united via national societies. One research focus of the funded projects comprises chronic pain conditions, e.g. low back pain, migraine or neuropathic pain. Most projects combine preclinical with clinical research in both, a translational concept or its opposite, i.e. in a bedside-to-bench direction that obtains its principal information from human data and uses laboratory experiments not to generate new hypotheses but to verify those obtained by clinical observation (L€ otsch and Geisslinger, 2010). The eight projects (Table 1 and Fig. 1) will be summarized in the following paragraph in the succession of their appearance at the FP7 website at http://ec.europa. eu/research/health/medical-research/brain-research/l_ coor_en.htm and based on the websites of single projects or personal communications from project speakers.
Eur J Pain 19 (2015) 595--600
595
EU FP7 pain funding
(A) Chronic low back pain, described as a discomfort condition in the local region around the posterior ribs and upper pelvis, affects an estimated 15–45% of the population at some point in life (Andersson et al., 1993; Van Tulder et al., 1995) and may become persistent when symptoms endure longer than 6 weeks and as ‘chronic’ when pain persists beyond 12 weeks (Krismer, 2007). The PAIN-OMICS project aims at the stratification of patients with low back pain. This multidisciplinary consortium will use a complex systems biology approach at the understanding of low back pain in a high-dimensional data set from more than 5000 patients. This project aims at prospectively establishing new genomic, epigenetic and glycomic (i.e. study of all glycan structures from a cell type or an organism) approaches to identify novel diagnostic and prognostic biomarkers and new therapeutic targets that could predict the risk that acute low back pain becomes chronic. (B) Migraine, typically characterized by recurrent moderate to severe headaches, autonomic dysfunction and sometimes aura symptoms, affects an estimated 15% of the population at some point in their life (Stovner et al., 2007). Currently, approved medications are only moderately effective and the particular need of effective prophylactic treatments to prevent attacks and chronification is poorly met. This owes to the incomplete understanding of the trigger mechanism of migraine attacks and of the reasons why in some patients their frequency increases. To narrow this gap of knowledge, the EUROHEADPAIN approaches the pathomechanisms and treatment options of migraine and its chronification by employing established and evolving human and preclinical research models to identify pathways and biomarkers of migraine attacks and to decipher the modulatory effects of brain circuitries on trigeminal processing, sensitization and chronification. (C) Neuropathic pain develops as a result of lesions or disease affecting the somatosensory nervous system either in the periphery or centrally (Baron et al., 2010). Up to 8% of the European population is affected and has often a great impact on their quality of life (Torrance et al., 2006). Disease or anatomy-based classifications of neuropathic pain comprise painful focal, multifocal or generalized peripheral neuropathies, central pain syndromes, complex painful neuropathic disorders and mixed pain syndromes (Baron et al., 2010). Neuropathic pain is considered to be one of the greatest challenge for pain research and therapy, as current treatment options are sparse mainly consisting of a combination of opioids and re-purposed antidepressants and 596 Eur J Pain 19 (2015) 595--600
€tsch D. Kringel, J. Lo
anti-epileptics that reduce the pain yet, but neither abolish it in most patients, nor prevent its evolvement towards chronification following nerve injury. The complexity of neuropathic pain is reflected in the funded projects that pursue several approaches comprising the development of sensory feedback tools for phantom limb modulation, the study of neuroinflammation and glial activation, of non-coding ribonucleic acids, sodium channels or the nerve growth factor, or the cross-validation of innovative chronic pain models and biomarkers in preclinical and clinical settings. One peripheral form is phantom limb pain, which often develops in association with the phantom limb syndrome, i.e. a perception of sensations in the amputated limb (Ramachandran and Hirstein, 1998), in about 60–80% of amputees (Sherman et al., 1984). Recent evidence suggests that phantom limb pain may be related to changes in neuronal plasticity in the cerebral cortex, which can be modulated by sensory input to the amputation zone (McCormick et al., 2014). This is intended to be exploited by the EPIONE consortium for developing a natural sensory feedback for phantom limb modulation and therapy. The project aims at offering technological solutions that will invasively or non-invasively induce natural, significant sensations to the amputee to restore the neuroplastic changes in the cortex and thereby control and alleviate phantom limb pain. The consortium will build solutions based on existing technologies, but presently only available in experimental settings. (D) The main hypothesis pursued by the GLORIA project is that neuroinflammation and glial activation play an important role in neuropathic pain and other chronic pain conditions and are involved in opioidinduced adverse effects such as tolerance. The project combines basic and clinical research, assesses markers of inflammation and glial activation in the cerebrospinal fluid and the brain (PET), and employs experimental pain models, genetic and epigenetic analyses. It aims at identifying complex high-dimensional phenotypes in more than 1000 pain patients as a basis to explain the symptoms and analgesic responses and to develop a biomarker profile for clinical conditions. This will be used to engineer new molecules providing novel analgesics with a better efficacy and safety profile than the therapeutic agents which are currently available. (E) Non-coding ribonucleic acids (ncRNAs) comprise a heterogeneous group from short- to mediumlength RNA molecules among which several members play important roles in the regulation of © 2015 European Pain Federation - EFICâ
€tsch D. Kringel, J. Lo
EU FP7 pain funding
Table 1 Pain-related projects that receive support from the European Union within its Seventh Framework Programme (FP7/2007–2013). The list has been taken from the official site of this programme at http://ec.europa.eu/research/health/medical-research/brain-research/l_coor_en.htm where further details including speaker’s names and addresses can be obtained, if not from the web representations of the single project showed in this table. The succession of projects corresponds with their appearance in that original document. Project title (A) PAIN-OMICS: Multidimensional omics approach to stratification of patients with low back pain (B) EUROHEADPAIN: Mechanisms and treatment of migraine and its chronification (C) EPIONE: Natural sensory feedback for phantom limb pain modulation and therapy (D) GLORIA: Understanding chronic pain and new druggable targets: Focus on glial–opioid receptor interface (E) NCRNAPAIN: Non-coding RNAs in neurogenic and neuropathic pain mechanisms and their application for risk assessment, patient stratification and personalized pain medicine (F) PROPANE STUDY: Probing the role of sodium channels in painful neuropathies (G) PAINCAGE: The NGF system and its interplay with endocannabinoid signalling, from peripheral sensory terminals to the brain: new targets for the development of next generation drugs for neuropathic pain (H) NEUROPAIN: Neuropathic pain: Biomarkers and druggable targets within the endogenous analgesia system
Project coordinator
Kind of chronic pain
Website
Massimo Allegri
Low back pain
http://www.painomics.eu
Michel Ferrari
Migraine
http://www.euroheadpain.org
Winnie Jensen
Neuropathic (phantom limb pain)
http://project-epione.eu
Eija Kalso
Neuropathic and other
http://gloria.helsinki.fi
Michaela Kress
Neuropathic
http://www.ncrna-pain.eu
Giuseppe Lauria
Neuropathic
http://www.propanestudy.eu
Antonino Cattaneo
Neuropathic
http://www.paincage.eu/
Rafael Maldonado
Neuropathic
http://www.upf.edu/neuropain
gene expression including those involved in immune and neuronal processes (Bartel, 2009; Ghildiyal and Zamore, 2009). Therefore, ncRNAs may act as critically important master switches for chronic pain, which the NCRNAPAIN consortium intends to exploit for risk assessment, patient stratification and personalized therapy approaches. The project aims at decoding these biological molecules’ role towards a better understanding of ncRNA regulation of nociception and endogenous analgesia and to identify and validate ncRNAs as molecular targets for pain prevention and pain relief. (F) Voltage-gated sodium channels play a key role in the transmission of nociceptive information and thus, for pain perception and chronification (DibHajj et al., 2010). The PROPANE project aims at resolving the genetic architecture of idiopathic and diabetic painful neuropathies through a complementary approach based on targeted sequencing of the five sodium channel genes expressed in the nociceptive pathway and identification of new targets by © 2015 European Pain Federation - EFICâ
unbiased whole exome sequencing and transcriptome assay. Its main objectives include to achieve a stratification of patients with high-risk to develop neuropathic pain by the discovery of novel biomarkers and to identify novel molecular targets for drug development. (G) The nerve growth factor (NGF) is a neurotrophin, which is critical for development and survival of neuronal cells (Barde, 1990). Variants in the nerve growth factor gene (NGFB) have been associated with a loss of pain perception (Hilz, 2002) suggesting its potential suitability as a novel drug target for the treatment of neuropathic pain, which is supported by the additional involvement of NGF in the modulation of endocannabinoid signalling known as a further player in neuropathic pain (Keimpema et al., 2013). At this point enters the research of the PAINCAGE consortium whose members aim at investigating strategies for the treatment of neuropathic pain based on the NGF system and its interplay with endocannabinoid signalling. The project addresses mechanistic Eur J Pain 19 (2015) 595--600
597
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€tsch D. Kringel, J. Lo
Figure 1 Geographic map of Europe showing the locations of the active pain research projects that receive active funding within the European Union Seventh Framework Programme (FP7/2007–2013). The locations are shown as spots coloured according to the eight consortia where the specific project belongs. The central part of Europe has been magnified for better visibility of the map. Not shown are collaborators outside the continent, i.e. in Indianapolis (EPIONE), Boston (EUROHEADPAIN) and New Haven (PROPANE), United States, and Brisbane (EUROHEADPAIN), Australia. The map was created using the libraries ‘ggmap’ (http://cran.r-project.org/web/packages/ggmap/index.html) and ‘car’ (http://cran.r-project.org/ web/packages/car/index.html) in R (version 3.0.2 for Linux; http://CRAN.R-project.org/). The underlying map was imported as the ‘Europe’ Map from Google Map Data ©2014, Basarsoft, Google Imagery ©2014 terra metric, 6 Dec. 2014.
bases for the development of already identified second-generation therapeutics, new molecular targets for drug development and biomarkers. (H) A major handicap for the finding of effective cures for neuropathic pain is the poor predictive 598 Eur J Pain 19 (2015) 595--600
validity of currently available preclinical chronic pain models (Mogil, 2009) that do not simulate the multidimensional and highly variable (Maier et al., 2010) clinical phenotype. The NEUROPAIN consortium therefore focuses on the validation of new preclinical © 2015 European Pain Federation - EFICâ
€tsch D. Kringel, J. Lo
EU FP7 pain funding
Table 2 Detailed localizations of the table with the research groups involved in the pain-related projects that receive support from the European Union within its Seventh Framework Programme (FP7/2007–2013). See also Table 1 and Fig. 1 for further details. Project title
Participant Country/City
Project title
Participant Country/City
(A) PAIN-OMICS
Italy/Parma Belgium/Genk Croatia/Zagreb Italy/Pavia United Kingdom/London Germany/Munic Netherlands/Rotterdam Croatia/Zagreb France/Noisy Le Grand United States/Winston-Salem Australia/Joondalup Netherland/Leiden ge Belgium/Lie Germany/Hamburg Finnland/Helsinki Australia/Brisbane Italy/Trieste Germany/Erlangen Denmark/Copenhagen United Kingdom/London Denmark/Aalborg Italy/Rome Switzerland/Lausanne United States/Indianapolis Sweden/Lund France/Montpellier France/Nice Germany/Freiburg Spain/Barcelona Finland/Helsinki Sweden/Stockholm Germany/Frankfurt Sweden/Lund Estland/Tartu
(E) NCRNAPAIN
Austria/Innsbruck Germany/Heidelberg €rzburg Germany/Wu Germany/Mainz €cken Germany/Saarbru United Kingdom/London France/Bordeaux Czech Republic/Brno Italy/Rome Denmark/Kopenhagen Israel/Jerusalem Italy/Milano Netherlands/Maastricht United States/New Haven United Kingdom/Manchester Germany/Berlin France/Paris
(B) EUROHEADPAIN
(C) EPIONE
(D) GLORIA
models to evaluate the electrophysiological, behavioural, emotional and cognitive manifestations of neuropathic pain and the effectiveness of novel analgesic compounds, with special attention on biomarkers and molecular targets for drug development within the endogenous analgesia system. In concert with clinical studies and genetic approaches, a translational focus will be set based on cross-validation of the findings in preclinical and human observations. Current EU funding supports preclinical and clinical studies of chronic pain in its various clinical facets, of which the most prevalent conditions will be analysed with respect to biomarkers, genetics and epigenetics, functional magnet imaging and other contemporary methods and readouts. This comprehensible clinical © 2015 European Pain Federation - EFICâ
(F) PROPANE STUDY
(G) PAINCAGE
(H) NEUROPAIN
Italy/Rome Denmark/Aarhus Austria/Vienna United Kingdom/Sandwich United Kingdom/London Spain/Salamanca Italy/Milano Italy/Pisa France/Paris Spain/Barcelona United Kingdom/London United Kingdom/Salisbury France/Illkirch Germany/Bonn Germany/Berlin Poland/Cracow Iceland/Reykjavik Finland/Helsinki
neuroscience of pain will be accompanied with preclinical assessments using the contemporary repertoire of bio-medical and bio-informatics and computer science methods. Owing to the funding and the expertise gathered in the consortia, in the next several years the results will begin to emerge. Acknowledgements This paper was written using Free Software programs on office and portable PCs running GNU/Linux. This communication is a contribution of the GLORIA consortium funded by the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 602919 (JL). The authors are beneficiaries of this funding.
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The authors have declared that no further conflicts of interest exist.
Dario Kringel, J€ orn L€ otsch Institute of Clinical Pharmacology, Goethe – University, Frankfurt am Main, Germany Correspondence J€ orn L€ otsch Email: [email protected] Funding sources This communication is a contribution of the GLORIA consortium funded by the European Union Seventh Framework Programme (FP7/2007 – 2013) under grant agreement no. 602919 (JL). The authors are beneficiaries of this funding. Conflicts of interest None declared.
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