There is increasing recognition of the role of neuroimmune factors as contributors to persistent pain but the mechanisms behind this are still being teased out. 

A recent article in Musculoskeletal Science and Practice provides an overview of emerging neuroimmune factors involved in persistent pain and the implications for evaluation, diagnosis and clinical management. 

The authors – Dr Scott Farrell FACP, a Specialist Research Physiotherapist (as awarded by the Australian College of Physiotherapists in 2024) based at RECOVER Injury Research Centre at the University of Queensland, and his two international colleagues, Dr Colette Ridehalgh (a physiotherapist and researcher at King’s College London) and Dr Joel Fundaun (a postdoctoral fellow and physiotherapist at Stanford University) – note that understanding the physiological mechanisms underpinning pain may lead to better diagnostic and management approaches and targeted treatment opportunities. 

From a physiological perspective, following an acute musculoskeletal injury such as injury to the ankle or neck, the body responds with a normal inflammatory immune response. 

Immune mediators including cytokines and other molecules are released locally and systemically and can sensitise the nociceptors – the nerve endings that signal to the brain that an injury has occurred – leading to pain as a protective response. 

Typically, this settles down after a time and the pain lessens. 

‘Normally there’s a resolution of inflammation and everything settles down as the tissue repairs but in some cases, we see an ongoing low-grade inflammation and that is associated with ongoing sensitisation,’ Scott says. 

Researchers, including Scott and his colleagues, are looking for evidence – for example, via imaging, sensory testing and identifying specific markers in the blood – to explore how the immune and nervous systems may interact and contribute to persistent musculoskeletal pain. 

Quantitative sensory testing is being used to identify subtle mechanical, thermal and electrical somatosensory dysfunction; specialised imaging techniques have been developed to explore and assess nerve pathophysiology in more detail; and skin biopsies can visualise the peripheral nervous system directly to identify reduced nerve fibre densities. 

The use of blood markers of inflammation such as C-reactive protein, tumour necrosis factor and other inflammatory molecules or of nerve injury (neurofilament light chain) is also being studied. 

The answers are complex and confirm that persistent pain can have elements of both nociceptive and neuropathic mechanisms. 

‘When I studied physiotherapy at university, we talked about mechanical back pain, mechanical neck pain, but I think more and more there’s an accumulating set of data suggesting that even in conditions that aren’t technically neuropathic, we see evidence of changes in the nervous system function and structure and we also see evidence of low-grade inflammation in conditions that aren’t classically inflammatory. 

‘But it’s all a long way from clinical application. 

‘So what’s going on?’ 

From a clinical perspective, it’s too early to put the research into practice – the techniques and measurements used for research studies are mostly not suitable for use in the clinic at this point. 

However, Scott says that neuroimmune factors are another consideration when thinking about the mechanisms of persistent pain and in building a picture of a patient’s persistent pain. 

‘When people are pondering some of the mechanisms underlying our patients’ pain, we need to be mindful that there are potential neurological and immunological contributions to the conditions we treat. 

‘It’s probably not something we’d investigate from a clinical perspective as physiotherapists just yet, but it’s something to be aware of – particularly in people with, say, cardiovascular disease or high BMI or low levels of physical activity or depression or other factors that we know are associated with low-grade inflammation. 

‘Neuroimmune pathways might be mechanisms by which a range of comorbid conditions that affect our patients could be contributing to the pain they experience.’ 

It may also be applicable to our knowledge of how some of the treatments that physiotherapists use might work. 

For example, exercises are commonly prescribed as a treatment for musculoskeletal pain, under the assumption that the reduction in pain comes from better muscular support of the affected joint or body part. 

‘Exercise could partly be working via its anti-inflammatory effect. 

‘Maybe some of our treatments, like exercise or even psychological stress modulation techniques, might improve pain through a pathway where we’re decreasing inflammation. 

‘While we might have thought in the past that this exercise might help with a condition by increasing muscle strength or joint range of motion or similar, a piece of the puzzle might actually be that when people are exercising, their blood inflammatory marker levels decrease, that reduces sensitisation of their nociceptors and what do you know, they feel less pain.’ 

From research and clinical perspectives, he thinks investigating the mechanisms underlying successful treatments might be a useful direction for researchers to consider. 

‘Understanding how these concepts fit into our clinical practice is pretty important and can inform how we refine existing treatments and develop new approaches.’