Pain Centre Versus Arthritis

2nd Versus Arthritis: Pain Research in the UK conference Workshop outputs

Meeting date: 9th September 2020

Dr Julie Jones-Diette & Dr Stephanie Smith

Overview of the day

The conference hosted by Pain Centre Versus Arthritis at the University of Nottingham was an active and educational day of presentations, posters, workshops, and a provocative plenary lecture by Prof Andrew Rice of Imperial College London.

View a copy of the presentation 

The conference combined UK clinical and preclinical researchers in musculoskeletal and other forms of chronic pain within a virtual setting. The themes on the day included Models of Pain, Measurement of Pain, Psychological Mechanisms, Pain Biomarkers, Brain Networks, Functional Connectivity and Novel Targets for Treatment.  The meeting brought together research leaders and early career researchers to discuss, establish and consolidate collaborative networks, and to shape future research direction.

Workshops

The main aim of these sessions was to allow smaller group discussions on specific topics and to share and learn from each other’s experiences. Sessions were chaired and commenced with an overview of the topics, after which general discussion was encouraged.

Outputs

Workshop 1 – Pain Models and Measurements of Pain

What are the challenges and successes of quantifying pain responses in human and animal models, how do we overcome translational barriers?

Chaired by Prof David Walsh & Dr Shafaq Sikandar, Facilitation – Stephen Woodhams

Questions for discussion

Q1. How is pain measured in humans and animal studies?

Q2. Are there discrepancies between how we define pain and what we measure as pain?

Q3. What are the key strengths and weaknesses of those measurement tools?

Q4. Which aspects of pain are not adequately measured in humans or in animals using standardised tools?

Q5. How do measurements map to neural correlates of pain?

Q6. Is it more important to model disease pathogenesis or robust hypersensitivity?

Q7. How do we improve the bi-directional translatability between animals and humans?

Discussion points

1. How is pain measured in humans and animal studies?

  • Self report: NRS, VAS
  • Ongoing pain and evoked pain
  • Reflex behaviours
  • Weight-bearing
  • PWT
  • Gait
  • Emotional; affective; conditioned place preference
  • Naturalistic behaviours: non-evoked
  • Burrowing, nesting, digging
  • What is the effect of sensory and emotional components to these behaviours?
  • Ongoing pain markers; c-fos, imaging of DRG neurons
  • Neurophysiology; stimulus-induced neuronal activity

2. Are there discrepancies between how we define pain and what we measure as pain?

  • Sensory and emotional
  • Outcomes largely sensory

3. What are the key strengths and weaknesses of those measurement tools?

Strengths and weaknesses of measurement tools
  Animals Humans
Robust and reproducible   X
Can define start and end  X  -
Homogeneous     

 4. Which aspects of pain are not adequately measured in humans or in animals using standardised tools?

  • Not all studies assess range of modalities; reliance on single outcomes which might differ between studies (human/animal)
  • Breakthrough and ongoing pain difficult to model in animals
  • Can’t ask animals what their pain is
  • Do animals `pretend’ when undertaking a behavioural test, or learn during behavioural studies

5.  How do measurements map to neural correlates of pain?

  • Neural correlates in animals often investigated under anaesthesia
  • Map behaviours to electrophysiology, imaging, molecular etc.

6. Is it more important to model disease pathogenesis or robust hypersensitivity?

  • Models of pain aren’t necessarily models of disease (e.g. MIA or carrageenan joint injections)
  • Value of using multiple models rather than relying on a single model to ensure generalisability
  • Need robust hypersensitivity to enable robust findings with small numbers of animals

7. How do we improve the bi-directional translatability between animals and humans?

  • Shared outcomes between preclinical and clinical pain measurement
  • Holistic measures including both sensory and affective components of pain
  • Homogeneous patient/animal populations; stratification and subgrouping

Round up and take-home messages for Workshop 1

  • Measuring pain differently in animals and humans
  • Sensory and emotional or largely sensory
  • Not looking at a range of modalities
  • Models of pain are not models of disease, need for robust models of hyposensitivity
  • Shared outcomes in preclinical and clinical pain measurement
  • Homogenous patient/animal populations
 

Workshop 2 – Psychological Mechanisms of Pain and Brain Networks

Can we achieve a step-change in knowledge of pain mechanisms by greater integration of the outcomes of psychological research and brain imaging?

Chaired by Prof Dorothee Auer & Prof Tamar Pincus, Facilitation – Amanda Lillywhite & Sara Goncalves

Questions for discussion

Q1. What are the most promising avenues for combining methodologies in pain research today?

Q2. How do behavioural methodologies complement and advance imaging research- can you give an example?

Q3. How informative are brain signatures as representation of mental states in pain research?

Q4. What are the key transdiagnostic behavioural factors that explain comorbidity of pain, depression, anxiety and how might they be identified by neuroimaging?

Q5. How can neuroimaging be used to study the multidimensional effects of complex interventions to alleviate pain?

Round up and take-home messages for Workshop 2

  • Multiple discipline discussions early on at the start of the project
  • Behavioural animal models
  • Wider and multiple ways to measure outcomes and patients to choose outcomes
 

Workshop 3 – Biomarkers and Novel Targets for Treatment

What biomarkers of pain are there, how can they be developed and validated? Can pain biomarkers aid the identification of novel targets for treatment?

Chaired by Prof Victoria Chapman & Prof Andrew Rice, Facilitation – Peter Gowler

Questions for discussion

Q1. What features does a pain biomarker need?

Q2. What are the purposes of a pain biomarker?

Q3. What tests are needed to ensure that pain biomarkers have clinical utility? Do they need to generalisable?

Q4. What is the rationale for a composite pain biomarker? What foundational scientific knowledge is required to be able to attribute weighting to individual biomarkers when they are combined to create a composite biomarker?

Discussion points

  • Need to consider the purpose of a biomarker and why we might want one.
    • Stratification for clinical studies
    • A surrogate for chronic pain
    • One that is relevant to pain rather than the broader disease
    • Use of multiple biomarkers to increase robustness- composite biomarker
  • Wet Biomarkers
    • Which biofluids are used and how clinically useful / easy is it?
  • Need robust measures as large dynamic range in people
  • Assay design that is translationally relevant and scalable
  • Need longitudinal data rich studies including measurement of biomarkers to determine reliability
  • Taking biomarkers back to the animal models may be  hard to achieve, needs common protocols and multi centre animal studies

Round up and take-home messages for Workshop 3

  • Purpose of biomarker and prediction of risk of pain
  • Efficacy biomarkers
  • May have different biomarkers
  • Robust biomarker of pain rather than disease - could be useful for patient stratification – may  increase chances of positive outcome
  • Pre clinical studies should be informed by clinical studies
  • Need for longitudinal studies and if/how it changes over time and how pain changes over time and how robust those biomarkers are
  • Reliable assays
 

Workshop 4 - Predicting pain and treatment response

What are the predictors of chronic pain and do they differ across different conditions? Can we predict response to targeted treatment?

Chaired by Prof. Weiya Zhang & Dr Gareth Jones, Facilitation – Dan McWilliams & Wendy Chaplin

Questions for discussion

Q1. Is secondary prevention possible, in chronic pain?

Q2. Does the immediate response to pain predict chronicity?

Q3. Can we capture non-specific treatment effects to amplify treatment response?

Q4. What is treatment response?

Q5. What are we predicting, overall treatment response (ie, total pain reduction because of treatment), or specific treatment effect (pain reduction between treatment and placebo)?

Q6. Is randomised controlled trial a good method to predict treatment response?

Discussion points

  • Predicting total treatment effects rather than specific treatment effects
  • It is possible to fight chronic pain early there are a number of studies which show a number of predictors of progression
  • Phenotypic differences between people with central pain versus peripheral pain - Predictors of chronicity maybe different between these groups and certainly seems to be some evidence of patients with central sensitisation would be more likely to progress to chronic and persistent pain, what's not clear perhaps is how much of what we know applied to all pain conditions and indeed all patients.
  • Individual patients and personalised medicine
  • Multi morbidities and how we manage these, or rather how we imagine we manage patients who have multi morbidities you know pain may come from many sources inflammation may come from many sources - speciality-specific-silos -  you see a rheumatologist you get a rheumatology opinion you see a cancer specialist you get a cancer opinion however it accepted that multi morbidities go up pain outcome goes down for a poor response
  • Treatment response in particular the difference between a specific treatment response to an agent for such sort of response that you may see in a placebo controlled drug trial more actually what happens in patients of course if you get a treatment response in the context of other things - there was some work to show that ~75% of people have non specific response
  • Whether we can exploit non specific effect - look at predictors of non specific effects that as much if not more than looking at specific response to treatment
  • Medical schools and the postgraduate medical training in many specialties has a very low focus on pain - we need to move to a more patient centred approach

Round up and take-home messages for Workshop 4

  • Identification of chronic pain early important for preventing secondary pain
  • Pain phenotypes - central sensitisation more likely to lead to chronicity
  • Multimorbidity and pain in other contexts
  • 3/4 of treatment effect is non-specific treatment effect
  • Treat pathology with the assumption the pain will decrease
  • RCT good for efficacy
 

Pain Centre Versus Arthritis

Clinical Sciences Building
City Hospital
Nottingham, NG5 1PB

telephone: +44 (0) 115 823 1766 ext 31766
fax: +44 (0) 115 823 1757
email: paincentre@nottingham.ac.uk