Complex regional pain syndrome (CRPS) is an intractable condition associated with long-term pain and disability and detrimental effects on work, relationships and quality of life. Although many treatment approaches have been tried, at best they provide only limited benefits often at the cost of significant side effects. As CRPS is a chronic condition that requires ongoing treatment, an advance in treatment efficacy not only would decrease personal suffering but would also reduce the burden on over-stretched pain management services. Despite recent advances in clarifying early neuro-immune disturbances in CRPS, mechanisms that maintain chronic pain remain unclear. Unfortunately, this has hampered the development of effective treatment regimens for this debilitating disorder.
In complex regional pain syndrome (CRPS), hyperalgesia often extends beyond the CRPS-affected limb to encompass other sites on the ipsilateral side of the body. In addition, discomfort evoked by noise and light is greater on the ipsilateral than contralateral side and may exacerbate pain in the affected limb. These observations suggest that nociceptive processing is disrupted within the central nervous system in CRPS, and that this disruption involves sites of convergence of sensory and nociceptive pathways such as the thalamus and primary sensory cortices. We believe that this disruption is due, in part, to failure of ascending and descending inhibitory pain controls (e.g., in subcortical and spinal pathways regulated by the ipsilateral locus coeruleus).
In this project, electroencephalography (EEG) and pupillometry will be used to investigate neural mechanisms of pain modulation within the brainstem, thalamus and somatosensory cortex in real time in patients with CRPS. We will use this direct approach to explore whether failure of brainstem pain modulation processes to effectively regulate thalamo-cortical communication mediates hemilateral hyperalgesia.
Despite recent major advances in clarifying neuro-immune disturbances in CRPS, mechanisms that maintain pain remain unclear. From this perspective, identifying the source of sensory disturbances in CRPS is crucial because, once mechanisms are better understood, these mechanisms could be targeted to more effectively manage sensory disturbances and pain. The studies in this project will be the first to use advanced neurophysiological techniques to systematically examine subcortical processing of nociceptive stimuli in CRPS and to examine links with brainstem activation (reflected by pupillary responses) and pain. This study will help to clarify the source of sensory disturbances and pain in CRPS and, in turn, will encourage new approaches to treating this intractable complaint.
Dr Philip Finch, Professor Peter Drummond, Dr Hakuei Fujiyama, Murdoch University, WA, Dr Flavia Di Pietro, Curtin University, NSW.
The project was awarded $A65,323 through the ANZCA research grants program for 2022.
Complex regional pain syndrome (CRPS) is a chronic debilitating disorder that can develop after limb fracture or even after minor injuries such as a sprain. Instead of healing progressing normally, pain increases and may extend beyond the injured site. As the condition evolves, the limb often becomes extremely sensitive to light touch and to minor changes in the environment (e.g., temperature changes, movement or even loud noises). In addition, sensitivity to pressure, warmth, cold and light touch increases not only in the painful limb but also at other sites on the painful side of the body.
In our previous work, we found that sensitivity to noise and bright light was greater on the symptomatic than non symptomatic side in people with CRPS. Together with the spread of sensitivity in the affected side of the body, this suggests a failure by the central nervous system to properly regulate sensations on the affected side. We believe that this failure involves sites within the brain where sensory and pain messages converge (the thalamus and primary sensory areas of the cerebral cortex). Furthermore, we believe that this failure to regulate normal sensory experiences stems from a malfunction in centres within the brainstem that act as a "volume control" on messages that pass through the thalamus - that is, signals, including pain, are amplified inappropriately, and normally-painless sensations become tinged with pain.
The aim of this project was to see whether we could find evidence to support this idea - that failure of pain control centres in the brainstem to properly regulate pain makes exposure to bright light uncomfortable in people with CRPS.
We found that the early part of the visual evoked potential, corresponding to increased neural activity in the thalamus, differed between CRPS patients and controls. This difference in neural activity might reflect a failure of brainstem and mid brain inhibitory pain controls to regulate nociceptive signals.
Our findings support the hypothesis that disruption of pain processing in subcortical areas of the brain alters the perception of normally innocuous sensations and contributes to pain and other symptoms in CRPS. This highlights the importance of clarifying the source of this disruption to encourage the development of treatments that reset this failed circuitry.
Drummond PD, Finch PM. Complex regional pain syndrome and migraine: clinical relationships and possible common aetiology. Cepha/algia Accepted for publication November 2025.
Presentations:
Drummond PD. Regional pain distribution in CRPS is associated with sensitisation in multiple sensory modalities. Australian Pain Society conference, 2024. Drummond PD. Pain distribution in CRPS. WA Pain Education webinar series, 2024. Finch PM. The Spread of symptoms in Complex Regional Pain Syndrome, including to cranial nerves. ANZCA Faculty of Pain Management, Spring meeting, 2025.