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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 3 - DOLORisk (DOLORisk: Understanding risk factors and determinants for neuropathic pain)

Teaser

Summary

Neuropathic pain (NP) arises as a consequence of a disease or lesion in the sensory nervous system. NP affects 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 involves a complex interaction between genetics, environmental and clinical factors in a vulnerable individual.
The 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 NP 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 firm platform to improve diagnosis and stratify patients according to risk profile, employ preventive strategies and develop novel therapeutics. To achieve this, we are collecting data on a wide range of potentially relevant risk factors from patients with varied causes for developing NP (diabetes, surgery, trauma). We are collecting detailed clinical and psychosocial information as well as 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, in order to validate molecular pathways contributing to chronic pain. Using this information, we will determine if patient stratification can predict NP risk and progression, and we will develop a risk model combining measurable genetic and environmental factors.

Work performed

1 Harmonisation
Questionnaires and examination protocols were harmonised across the recruitment centres to guarantee compatibility at the analysis stage. The data is centralised in a database hosted in Dundee and is checked on a regular basis for inconsistencies. A core protocol applies to Scottish population cohorts which are contacted by post, and the other centres implement an extended, more detailed protocol. Consensus meetings allowed us to define these protocols, and more recently to agree on our case definitions and these have been complemented by videos accessible via the DOLORisk website to enable standardisation of examination technique and conditioned pain modulation. Based on the DOLORisk protocol, a questionnaire has been designed for UK Biobank to collect more accurate chronic pain information which will enable a further validation cohort for DOLORisk.
2. Recruitment
Recruitment has caught up after initial delays in obtaining ethics approvals and we have now met our initial recruitment targets. The DOLORisk cohorts cover a variety of neuropathic pain conditions, such as diabetes, chemotherapy, surgery, traumatic nerve injury, small fibre neuropathy, and rare pain phenotypes. Diabetes is the main point of focus of DOLORisk and we are setting up collaborations with other projects that have a similar focus and comparable phenotypic data.
3 Initial analysis
Based on data from UK Biobank and the Scottish cohorts, initial candidate gene analysis and genome-wide association studies found promising results. These findings will be replicated thanks to our growing recruitment numbers with more detailed phenotyping data. With data from the Oxford cohort, we identified new mutations in sodium channels specific to painful diabetic neuropathy. EEG data showed significant differences in the connectivity between pain processing regions, and Technion produced models of event-related analysis and resting state analysis. GENT have completed a review on screening tools for psychosocial risk factors, finding a high risk of bias in many studies, as well as incomplete information making the assessment difficult. Implementing examination of psychosocial factors in the prospective development of neuropathic pain in the population cohorts collected in Dundee suggest that depression, pain catastrophizing and adverse childhood events are important risk factors.
4 Dissemination
Our website is updated regularly with news items, publications and events. The DOLORisk consortium was present at major international conferences, regional meetings and policy events (such as a recent UKRI/Versus Arthritis pain discovery platform meeting in London). The DOLORisk protocol has been published on Wellcome Open Research, an innovative open-access platform, and we have contributed to another 25 publications so far.

Final results

The risk and impact of NP represents a complex interplay of environmental and genetic factors which impinge on individual factors such as the emotional and cognitive state. The DOLORisk common protocol was defined to unpick these factors contributing to inter-individual variation. The size of the cohorts and the breadth and depth of our multidisciplinary approach ranging from molecular mechanisms to psychosocial factors have never been realised in the field of NP. We have now collected the largest and most highly phenotyped cohort of NP patients meaning that DOLORisk is a unique research programme . Our protocol is a step forward in the study of NP as it integrates multiple approaches in a single scheme: we collect information on clinical (WP1) and sensory phenotype (WP4), physiological biomarkers (WP5), and psychological and lifestyle factors (WP6), to be combined with a genetic analysis (WP2) on a number of patients that is unprecedented in the field of NP. Analysis of the Scottish population cohorts and UK Biobank data revealed two variants around the genes EPHA3 and SLC25A3. These variants provide novel insight into the pathogenesis of NP. These will be linked to molecular pathways and cellular pathophysiology (WP3). With this approach we have identified new mutations in sodium channels involved in painful diabetic neuropathy (Blesneac 2018) and other NP conditions such as non-freezing cold injury and congenital insensitivity to pain.
We will develop a risk stratification algorithm using the risk factors which we identify and test this at a population level (WP7). Such a risk model has not previously been developed within the pain field and could have an important impact on prevention and treatment: currently a major issue is the variability of treatment efficacy. A better understanding of the underlying mechanisms will allow for more targeted clinical trials. Researchers and companies will be able to use the risk algorithm to develop drugs that target a specific set of risk factors. As the algorithm will be available to practitioners, it will be easier in a clinical context to match a patient to a risk group and better target treatment. Clinical profiling will also be linked to the genetic findings. Such stratification will allow us to better predict which patients will respond to a given treatment. This will lead to more efficient pain management, personalised treatment, and a reduction in the social and economic consequences of living with chronic pain.