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DOLORisk Report Summary

Project ID: 633491
Funded under: H2020-EU.3.1.1.

Periodic Reporting for period 1 - DOLORisk (DOLORisk: Understanding risk factors and determinants for neuropathic pain)

Reporting period: 2015-07-01 to 2016-12-31

Summary of the context and overall objectives of the project

Neuropathic pain (NP) arises as a consequence of a disease or lesion in the sensory nervous system. NP is a common condition affecting 8% of the population and will present a rising health burden in the future. It results in significant morbidity, reduces quality of life and has a major deleterious impact on health in aging. However, not everyone develops significant NP following injury to the nervous system, and those who do develop it include a wide range of severity, impact and outcomes, and an unpredictable response to evidence-based treatment. This variation in pain prevalence and severity involves a complex interaction between genetics, environmental and clinical factors in a vulnerable individual.
The exact nature of risk factors for NP and their interaction are currently poorly understood and are the focus of DOLORisk. Identifying these risk factors will have a significant impact on health both in identifying vulnerable patients and potential for developing new treatment modalities. The project is highly translational and the starting point is the study of patients with or at risk of developing NP. Our aim is to understand pain pathophysiology in terms of risk factors and protective mechanisms ranging from molecular pathways to societal impacts. The desired impact is to provide a platform to improve diagnosis and stratify patients according to risk profile, employ preventive strategies and ultimately develop novel therapeutics. To achieve this, we are collecting data on a wide range of potentially relevant risk factors from patients with varied potential causes for developing NP (diabetes, surgery, trauma). We are collecting detailed clinical and psychosocial information, which we complement with specialised tests to determine the sensory and physiological profile of the patients. We are determining genetic variants that influence the development of NP, as well as the functional role of these variants in sensory processing, to validate molecular pathways contributing to chronic pain in patients. Using this information, we will determine if patient stratification can predict NP risk and progression, and we will develop a clinical risk model combining measurable genetic and environmental factors.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In the first 18 months our objectives were:

1) To establish a common protocol to collect data that will be comparable across centres
A consensus meeting was organised with the recruitment centres to define a common protocol and ensure that the data we collect is comparable across the DOLORisk centres, but also with previous and ongoing studies of NP. We agreed on a core protocol for Dundee to re-phenotype the population cohorts Generation Scotland and GoDARTS for NP; an extended protocol for deep phenotyping will be followed by the rest of the centres. Common procedures were introduced for clinical examination, quantitative sensory testing, threshold tracking and conditioned pain modulation, in order to reduce the variability between clinicians and across centres. Detailed guidelines on clinical examination were circulated by Oxford, QST training workshops of the German Network for the Study of Neuropathic Pain (DFNS) were attended by clinicians, a video protocol for CPM was produced by Technion, and calibration studies were coordinated by NT which have been implemented in those centres undertaking threshold tracking.

2) To obtain ethics approvals for the local DOLORisk cohorts
Oxford and Dundee submitted amendments to extend previously existing cohorts into DOLORisk, and these went through without difficulties, securing approval to re-phenotype 8,000 patients in the population studies and to recruit 600 patients in the diabetes cohorts at Oxford and Imperial. The other centres also made submissions for ethical review for the new DOLORisk cohorts. Local ethics committees were thorough in enquiring about the genetic component of DOLORisk and personal data protection which added some delays; all were ultimately approved and recruitment has started in all centres.

3) To set up a database to collect all centres’ data
Dundee and Oxford coordinated closely the creation of a bespoke database. A data entry system has been set up to collect information from the extended protocol and the clinical examination, while sensory profiling and nerve excitability data will be imported from Kiel and Barcelona. The system was carefully tested to ensure the data could be entered efficiently and with minimum errors.

4) To establish communication and dissemination tools
The DOLORisk website was published in January 2016 and updated regularly since then with news items, a list of publications and events of interest for researchers and organisations specialising in chronic pain. Members of the consortium were present at major conferences and high-level meetings on pain, such as the 2015 NeuPSIG Congress in Nice; the 2015 Congress of the European Pain Federation in Vienna; the 2016 IASP World Congress on Pain in Yokohama; the 2016 Symposium “Societal Impact of Pain” at the European Parliament, etc.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The risk and impact of neuropathic pain (NP) represents a complex interplay of environmental and genetic factors which impinge on individual factors such as the emotional and cognitive state and the ability to activate endogenous analgesic mechanisms (von Hehn et al., 2012). The starting point of DOLORisk was the definition of a common protocol to be able to unpick these factors contributing to inter-individual variation. The size of the cohorts studied and the breadth and depth of our multi-disciplinary approach have not previously been applied to NP. The DOLORisk protocol is key to the later stages of the project and represents a step forward in the study of NP, as it integrates multiple approaches in a single scheme. The protocol collects information on clinical (WP1) and sensory phenotype (WP4), physiological biomarkers (WP5) and psychological and lifestyle factors (WP6). All these factors have traditionally been studied separately in NP; bringing them together in a single protocol will improve patient stratification. This information will be combined with a genetic analysis (WP2) and the gene variants we identify will be linked to molecular pathways and cellular pathophysiology (WP3) which is highly innovative in the field of pain. We will develop a risk stratification algorithm using the salient risk factors which we identify and test this for validity at a population level (WP7). Such a model has not previously been developed within the pain field and could have an important impact on risk prevention and treatment.
We worked on improving the definition and grading of neuropathic pain with the IASP’s Neuropathic Pain Special Interest Group (NeuPSIG). A basic set of phenotypes to identify cases of possible NP and improve the reproducibility of genetic studies on NP was defined by an expert panel involving several DOLORisk members (van Hecke et al., 2015). The grading system to classify NP as possible, probable or definite was improved on to eliminate obstacles and uncertainties in the process (Finnerup et al., 2016). Technion and Imperial reviewed studies with conditioned pain modulation to evaluate the reliability of the technique and identify areas of improvement (Kennedy et al., 2016).

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