Modulatory Capacity: Biomarkers for pain sensitization and response to psychological treatment for pain

A recent UK study demonstrated that making treatment choices based on individual differences in sensory and psychological aspects of pain resulted in improved patient outcomes and lower medical costs. The proposed research also aims to direct patients to the best treatments, but aims for bigger improvements by precise measurement of mechanisms that make some individuals prone to chronic pain. Based on previous research, I hypothesize that individual differences in how the brain modulates information about injury from the body ("modulatory capacity") might tell us who is at risk of developing chronic pain and how we might best treat these high-risk individuals. A reliable measure of these individual differences could help clinicians steer patients towards the best treatments. This research aims to develop a modulatory capacity assessment battery (MCAB) using measures of negative emotion, pain responses and patterns of brain activation.

Previous studies have shown that measures of central pain modulation can predict who will develop chronic pain after surgery. These studies have used single measures and their rates of prediction are not optimized for clinical use. This project will collect a wide range of measures of brain function, pain responses and unhelpful attitudes about pain. This carefully chosen set of measures can will help us understand why some individuals are more susceptible to chronic pain and help us direct them towards treatments that are more likely to help them.

In order to test the utility of the MCAB in predicting who becomes sensitized to pain, we have developed an experimental model where participants are exposed to a series of painful stimuli over eight separate days. We will use the MCAB to identify individuals whose brains enhance pain responses over time. This experiment will help us understand the mechanisms that make some people more likely to develop persistent pain. Our eventual goal is to use this measure in clinical settings, to identify individuals at risk of developing chronic pain after surgery. This study will provide an important first step towards a future grant to examine the use of the MCAB in a clinical setting.

The ability to identify individuals at risk of developing chronic pain provides little advantage if we are unable to provide treatments. A low-risk and low-cost option for early intervention for individuals at risk of developing chronic pain is cognitive behavioural therapy (CBT). CBT has been shown to reduce suffering and disability related to pain. In the same experiment mentioned above, we showed that it reduced central enhancement of the pain response. We will use this same experiment to find out whether individuals identified by the MCAB as "high risk" (those showing increased sensitisation in response to prolonged pain) will be responsive to CBT. One potential use of these findings would be to identify individuals that might benefit from early intervention with CBT immediately after a painful surgery.

Why certain individuals develop chronic pain is an enduring clinical and scientific question. It has been demonstrated that psychophysical measures of central facilitation and inhibition of pain predict the development of chronic pain following surgery. On this basis, it has been proposed that individuals prone to central facilitation of pain represent a "pro-nociceptive phenotype". Other research indicates that high levels of negative affect might also predispose some individuals to persistent pain. Finally, neuroimaging findings demonstrate that functional connectivity of pain, emotion and reward regions can characterise individuals who develop chronic pain.

Taken together, these converging lines of data suggest that combining psychophysical, psychological and neuroimaging assessments might allow us to identify individuals at risk of developing persistent pain. This program of research will develop a multi-modal assessment battery for the ability to adaptively employ central pain modulation circuitry. This battery will be used within the context of an experimental model of prolonged pain exposure that we have developed. We will test the hypothesis that individuals with a pro-nociceptive phenotype will experience the greatest increase in pain sensitisation over time.

Importantly, it has been shown that individuals with a pro-nociceptive phenotype are most responsive to treatments aimed at mitigating central faciliatory processes, leading to the conclusion that identifying such individual might also help us direct them to appropriate treatment. We have shown that central facilitation of pain can be reversed with cognitive behavioural therapy. We will therefore test whether individuals with a pro-nociceptive phenotype will be most responsive to this intervention.

Realisation of these aims would contribute to an earlier and more proactive approach to treating pain before it becomes chronic, potentially streamlining pain management within the NHS and beyond.

Chronic pain has a devastating effect not only on the lives of those directly afflicted, but on society, through disability, lost productivity and medical costs. These personal and societal costs are compounded by time and money wasted on ineffective treatments. Previous research has demonstrated how even a rudimentary individual differences assessment can result in more effective and efficient treatments, with some individuals being steered away from treatments from which they are unlikely to benefit, while others are steered towards a more intensive and effective treatment regimen. Accordingly, we believe that a more comprehensive and mechanism-based assessment has the potential to stratify treatment even more effectively, resulting in direct savings to the NHS and increased patient satisfaction. The primary goal of this research program, therefore, is to develop and test a battery for assessing individual differences in the ability to utilize central modulatory circuitry in an adaptive and context appropriate manner, a variable referred to here as "modulatory capacity". This modulatory capacity assessment battery (MCAB) will be mechanism based (employing neuroimaging and behavioural measures known to reflect pain vulnerability) and clinically predictive (as previous research has demonstrated associations between individual measures and response to treatments aimed at altering central modulation of pain). We expect that the MCAB will identify individuals with a "pro-nociceptive phenotype", that is, individuals likely to experience centrally-mediated facilitation of pain, which has been associated with the development of chronic pain. We hypothesise that these same individuals will respond strongly to treatments aimed at reducing central facilitation. One such treatment is cognitive behavioural therapy. If these hypotheses are correct, it could help us move individuals identified as pro-nociceptive towards early intervention. As such the MCAB is expected to make tangible contributions to both basic and clinical pain science.

Towards this goal, this proposal will build on a collaboration that has already been initiated with Dr. Deepak Ravindran and Dr. Atul Kapila of the Pain Management Unit at the Royal Berkshire Hospital aimed at incorporating the MCAB into routine clinical practice. Within the three-year period of this grant we will begin establishing the clinical feasibility of the MCAB within a chronic pain population and collect pilot data that will support funding applications to run larger clinical trials. If, as we hypothesize, the MCAB show clinical utility, we aim to establish an assessment clinic in conjunction with the School of Psychology and the newly established Thames Valley Clinical Trials Unit. As we develop and disseminate this work, we expect it to impact treatment of post-surgical pain and other types of pain observed in the wake of physical trauma (e.g. work-related injury). This has the potential to reduce suffering of people living with pain, and to ease the huge financial burden of chronic pain on the NHS and the workforce.

The International Association for the Study of Pain has declared 2017 the Global Year Against Pain After Surgery. A mechanism-based approach to understanding why some individuals might be vulnerable (or resilient) to persistent post-surgical pain is highly timely. Our results will add to a growing effort to establish mechanism based classification schemes to influence diagnosis and treatment. These include an MRC-funded initiative at King's College to classify chronic pain according to mechanisms rather than location of pain. Together, these UK-based initiatives will contribute directly to a search for personalized treatment of persistent pain.