Diagnosis & Measurement of Pain

Conditioned Pain Modulation (CPM): To Be or Not To Be?

This house believes that conditioned pain modulation (CPM) is a useful tool for research and clinical work. This is based on many studies showing less efficient CPM in pain patients, especially in the nociplastic disorders, and on studies that show prediction by CPM of future pain after interventions such as surgery as well as response to pain treatment. Nevertheless, many studies show difficulties in test repeatability, and a lack of relevance of CPM to those clinical situations. In this debate the first opponent will review the data supporting the relevance of CPM, and the other opponent will review the data against. The discussion will attempt to put in order the available data, and draw some conclusions regarding the role of CPM in clinical research and clinical practice

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Conditioned Pain Modulation is a Real Physiological Phenomenon: Evidence for a Spinal Neuronalcorrelate in Translational Studies

The ‘pain inhibits pain’ phenomenon was originally described in anesthetized rodents, where it is possible to quantify functionality in the pathway – scientifically termed diffuse noxious inhibitory controls (DNIC) – as a decrease in the peripherally-evoked activity of spinal convergent neurons following application of a conditioning stimulus. Interestingly, such naturally occurring analgesia upon conditioning is also observed in conscious humans, and conditioned pain modulation (CPM) is the term coined by Professor Yarnitsky to describe the human counterpart of DNIC. The functionality of this system depends on multiple factors including attention to the test and/or conditioning stimulus, distraction, and mood among others. But at the heart of the pain inhibits pain phenomenon, whether being measured in wakeful humans or anesthetized rats, is a brainstem to spinal cord modulatory pathway that is sub-served by noradrenaline to reduce pain signal processing in the transmission center. This is clinically relevant since pharmacotherapies that restore an imbalance in monoaminergic transmission, such as duloxetine and tapentadol, have previously been shown to restore CPM in chronic pain patient populations. Crucially therefore, CPM is possible to apply as a biomarker in clinical trials if the patient cohort, and stratification therein, is accurately described.

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Conditioned Pain Modulation is Associated with Reliability Issues, Problems with Generalizability and Lacks Clinical Predictability

Conditioned pain modulation (CPM) can be assessed using a wide range of test modulates with different test-retest capabilities. Studies indicate that multiple factors such as sleep deprivations, opioid use and cognitive factors will impact the assessment. These factors are rarely controlled for, which comprises the test-retest reliability. Recent studies demonstrate that the temporal summation of pain (TSP) and CPM response in patients with chronic pain varies, which could be interpreted as some patients being more pain sensitive than others. Pretreatment TSP variability seems to independently predict treatment responses to standard pain treatments such as surgery, NSAIDs and exercise therapy and this seems to be a less consistent finding for CPM. Finally, the descending pain inhibitory pathways are serotonin- and noradrenalin-dependent. Studies have demonstrated that CPM predict the analgesic effect of duloxetine (a serotonin and noradrenalin reuptake inhibitory) and that duloxetine modulates CPM. Dr. Petersen and colleagues recently conducted an 18-weeks randomized placebo-controlled trial on duloxetine in patients with severe knee osteoarthritis and found no effects CPM and CPM did not predict the analgesic effect of duloxetine. Conclusively, these data suggest that CPM is unfit as a biomarker in clinical trials and suggest that research initiatives should be directed towards TSP.

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Novel Biomarkers in Painful Neuropathies – Recent Advances in Magnetic Resonance Imaging (MRI), Microneurography, and non-coding RNAs

This workshop focuses on novel biomarkers for peripheral neuropathy and neuropathic pain. In the first session Matthew Evans will discuss the development of MR neurography, and its application to some common neuropathies such as diabetic neuropathy. He will explore the current state of the art, share experience with high field (7 Tesla) imaging of peripheral neuropathies, and some recent application of these techniques to neuropathic pain. Andreas Themistocleous will then discuss how microneurography allow us to obtain functional data on small, nociceptive fibres, a population of nerve fibres which cannot be assessed by more traditional neurophysiological techniques. He will discuss how abnormalities in nociceptive fibres can be demonstrated in peripheral neuropathies and other painful conditions such as fibromyalgia. We finish with a talk by Michaela Kress on the differential expression of non-coding RNAs (ncRNA) and their potential roles in neuropathic pain and regenerative processes.

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Magnetic Resonance Imaging Biomarkers in Painful Neuropathies: A Focus on Diabetic Neuropathy and other Symmetrical Polyneuropathies

Peripheral neuropathies are common; diabetes mellitus alone affects around 8.8% of the world population, with around half developing neuropathy and a quarter of these having significant neuropathic pain which causes disability and reduced quality of life. However the pathomechanisms which lead to development of neuropathy and pain are incompletely understood. There are numerous techniques used to investigate these conditions, including neurophysiology and quantitative sensory testing, each of which has its advantages and drawbacks.

Despite widespread use of magnetic resonance imaging (MRI) in studying central nervous system (CNS) disease, the use of MRI to investigate peripheral neuropathies is still in its infancy, largely due to technological challenges including spatial resolution, although this has changed in recent years with the increased availability of 3 Tesla (T) and 7T systems. MRI at higher field strength can offer fascicular level resolution in peripheral nerves, offering the exciting possibility of developing MRI as a “virtual biopsy”. In MR neurography, combinations of T1, T2 and diffusion sequences are used to image peripheral nerves and has now been applied to numerous peripheral conditions including inflammatory, metabolic, infective, traumatic and compressive neuropathies. Here we review recent work on some common peripheral neuropathies, including applications to neuropathic pain.

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Microneurography to Study Nociceptive Fibre Changes in Painful Peripheral Neuropathies

Microneurography is the only neurophysiological technique that records neuronal activity directly from nerves in awake patients. The thin myelinated and unmyelinated nociceptive fibres, tested by microneurography, are not assessed by conventional nerve conduction studies and are responsible for sensing pain. Nociceptive fibres are heterogenous, they show different stimulus-response functions and some are mechanically-insensitive in the naive state. Recording from nociceptive fibres provides unrivalled insight into peripheral neuronal activity and how it can relate to chronic neuropathic pain; for example, study of nociceptive fibres in fibromyalgia patients identified hyperexcitability in C fibres and a possible new mechanisms for chronic pain in these patients.

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Non-Coding RNAs as Hub Regulators of Neuropathic Pain and Neuroregeneration

Nerve injuries activate inherent transcriptional programs in primary afferent neurons residing in the dorsal root ganglia (DRG), which are critical for the initiation of neuropathic pain. Members of the non-coding RNA (ncRNA) family, specifically the short microRNAs (miRNA) act as master switches orchestrating biological processes in both the immune as well as nervous system. Since miRNAs are emerging as important regulators of the reaction to injury it is important to understand the precise contribution and role of specific miRNAs associated with the pathogenesis of neuropathic pain vs. regenerative processes. As miRNAs promise unique and specific advantages for therapeutic interventions, the identification of specific miRNAs promoting or preventing neuropathic processes and the unraveling of their target genes and mechanisms of action are of critical importance and offer novel therapeutic perspectives for pain resulting from nerve injuries. Benefit for the patient may also emerge from the presence of disease related ncRNAs in blood cells and extracellular vesicles which may be exploited as liquid biopsies for diagnostic purposes. Studies exploring the potential of specific ncRNAs signatures as biomarkers indicative of neuropathic pain disorders are discussed.

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Back Translation of Functional, Pharmacodynamic Pain Biomarkers into Rodents

As part of the BioPain subtopic of IMI-PainCare, multiple pharmacodynamic (PD) biomarkers of nociceptive system function are being back translated from humans to rodents and their translatability assessed, specifically in relation to the effects elicited by the administration of three model compounds (lacosamide, pregabalin & tapentadol). Four primary assays are being utilized in this project: peripheral nerve excitability testing (threshold tracking), ii) somatosensory-evoked, spinal potentials (N13 response), (iii) EEG ± laser-evoked potentials (LEPs) and (iv) functional magnetic resonance imaging (fMRI). Here we will provide an overview of this effort, with a specific focus on comparisons between human and rodent LEPs. In brief, our work demonstrates that LEPs with features comparable to those recorded in humans can be reliably recorded in awake, freely-moving rats. Administration of the three model compounds significantly reduces their amplitude, with a temporal profile consistent with each drugs PK profile. The compounds also modulate concurrently recorded resting state spectral power and auditory evoked potential amplitude, providing additional insights into non-specific effects of the compounds on CNS function (e.g. sedation). With the aid of extensive PK and PD profiles generated for each compound (including within-subject PK & PD), we will present the PK-PD relationships describing these pharmacological effects.

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Deep Phenotyping to Improve our Understanding of Chronic Pelvic Pain

Chronic pelvic pain is common, affecting almost one quarter of women worldwide, with a significant impact on quality of life and high associated financial cost. The diagnosis of underlying pathology is difficult and frequently requires multiple surgical procedures often under different specialists. It is perhaps unsurprising therefore that the focus of biomarker research in this field has been non-invasive diagnostic tests. The TRiPP subproject of IMI-PainCare is taking a different approach, aiming to use biomarkers to identify underlying pain pathways rather than the presence of disease. This multi-site study integrates detailed phenotypic data with genomics and plasma proteomics and metabolomics in a cohort of almost 800 woman (556 with pelvic pain and 230 pain-free controls) and expands this data-set with additional questionnaires and psychophysical assessments in a subset. Additionally, our design allows us to specifically explore associations of endometriosis and of bladder symptoms. We will present results from integrative analyses of this rich dataset, determining key pathways underlying pain in women with pelvic pain and identifying clinically meaningful subgroups and associated biomarkers. Ultimately we hope this strategy will identify novel therapeutic targets, inform a more personalised approach to treatment and allow refinement of preclinical models to optimise drug discovery.

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Signature for Pain Recovery IN Teens (SPRINT): Biomarker Signature Detection in a Multivariate Dataset Leveraging Supervised Machine Learning algorithms

Up to 5% of adolescents suffer from debilitating, chronic musculoskeletal (MSK) pain affecting quality of life, school attendance, mood, and family function, and posing a significant economic burden. Only 40%-60% of adolescents with chronic MSK pain sustain significant improvements in clinical endpoints of pain severity and functional disability. Discovery of robust markers differentiating recovery versus persistence is essential to develop more resource efficient and patient-specific treatment strategies and to conceive novel approaches that benefit patients. Signature for Pain Recovery IN Teens (SPRINT), integrates four major domains: blood (immune markers), psychophysiologic (QST), imaging (brain structure and function), and patient report (demographic, physical, psychological) metrics. These selected metrics have robust associations with pain and function but have been limited by sample size, single metric assessment, and moderate effect sizes. This study represents the largest cohort of adolescents with chronic MSK pain deeply characterized to derive a prognostic biological signature of pain and functional recovery leveraging  a multivariate computational analysis pipeline which includes cross-validation, for the extraction of reliable results from this multilayered and complex dataset.

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