Understanding how pain is processed in the brain


Pain is a very common disabling condition. It consists of physical, psychological, social, emotional, and cultural contributors. This complex interaction of several factors makes pain unique to each individual and therefore, challenging to treat. The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage”.

Pain is historically linked to protection and safety. It is a perception that occurs in response to what the brain judges to be a threatening situation. To evaluate potential threats, the brain uses information from the body, along with previous beliefs and memories. In this way, pain is a protective response that can trigger useful changes in behaviour that protect from tissue damage or limit further harm. However, for some people, when pain persists for longer than usual healing time, pain does not perform a useful function. This is thought to be driven by unhelpful adaptations in the pain producing system (e.g. brain).

Pain can be categorised depending on how long it persists. Acute pain lasts for a short time (less than 3 months) and typically occurs following injury or surgery. Chronic pain is pain that continues beyond expected tissue healing time (usually 3 months) even after injured tissues are healed.

The Centre for Pain IMPACT at NeuRA conducts research on a range of different pain conditions to understand the mechanisms of pain and to improve pain management. The Centre for Pain IMPACT has conducted several groundbreaking pain research projects which numerous clinical practice guidelines have endorsed internationally. Our current projects are listed below.


What is the analgesic effect of EEG neurofeedback for people with chronic pain? A systematic review

Researchers: A/Prof Sylvia Gustin, Dr Negin Hesam-Shariati, Dr Wei-Ju Chang, A/Prof James McAuley, Dr Andrew Booth, A/Prof Toby Newton-John, Prof Chin-Teng Lin, A/Prof Zina Trost

Chronic pain is a global health problem, affecting around one in five individuals in the general population. The understanding of the key role of functional brain alterations in the generation of chronic pain has led researchers to focus on pain treatments that target brain activity. Electroencephalographic (EEG) neurofeedback attempts to modulate the power of maladaptive EEG frequency powers to decrease chronic pain. Although several studies provide promising evidence, the effect of EEG neurofeedback on chronic pain is uncertain. This systematic review aims to synthesise the evidence from randomised controlled trials (RCTs) to evaluate the analgesic effect of EEG neurofeedback.

The search strategy will be performed on five electronic databases (Cochrane Central, MEDLINE, Embase, PsycInfo, and CINAHL) for published studies and on clinical trial registries for completed unpublished studies. We will include studies that used EEG neurofeedback as an intervention for people with chronic pain. Risk of bias tools will be used to assess methodological quality of the included studies. RCTs will be included if they have compared EEG neurofeedback with any other intervention or placebo control. The data from RCTs will be aggregated to perform a meta-analysis for quantitative synthesis. In addition, non-randomised studies will be included for a narrative synthesis. The data from non-randomised studies will be extracted and summarised in a descriptive table. The primary outcome measure is pain intensity assessed by self-report scales. Secondary outcome measures include depressive symptoms, anxiety symptoms, and sleep quality measured by self-reported questionnaires. Further, we will investigate the non-randomised studies for additional outcomes addressing safety, feasibility, and resting-state EEG analysis.

MODULATE: Altering the brains sensitivity to pain

Pain is the single most common reason for seeking medical attention. Under normal circumstances, pain acts to signal injury and is a protective response that prevents further damage and promotes tissue healing. People differ not only in their ability to detect and tolerate pain, but also in their ability to recover from an injury, with some people experiencing pain that outlasts the duration of tissue healing. Interventions to treat or cure chronic pain have had limited success.

Recent research has identified a novel cortical biomarker that could identify individuals at risk of developing chronic pain, which could be used to identify individuals at high risk of transitioning from acute to chronic pain (PREDICT project). However, whether a causal relationship exists between this cortical biomarker and pain is unknown.

The pain biomarker is based on rhythmic patterns of electrical activity in the brain and is measured using electroencephalography (EEG). Previous research suggests that the speed of this rhythmic activity can be altered through the administration of nicotine. MODULATE will attempt to alter the speed of the brain’s rhythmic activity, using nicotine gum, and observe the impact on pain. The project will help determine whether a causal relationship exists between the biomarker and pain.


PREDICT: A novel cortical biomarker signature for predicting pain sensitivity

Temporomandibular disorder (TMD) is the second most common musculoskeletal pain condition and is associated with pain and tenderness of the jaw. Although a number of biological factors have shown an association with chronic TMD in cross-sectional and case control studies, there are currently no biomarkers that can predict the development of chronic symptoms. Because of the difficulty in treating chronic pain, development of brain signal predictive biomarkers is of growing interest.

The PREDICT project will aim to develop a predictive biomarker signature of pain severity and duration using two commonly available techniques – electroencephalogram (EEG) and transcranial magnetic stimulation (TMS) – and perform initial clinical validation in first onset TMD. The biomarker could have utility in identifying patients at high risk of transitioning from acute to chronic pain and has additional potential for clinical application in the treatment and prevention of chronic pain.

This project will be carried out in collaboration with a team at the University of Maryland, Baltimore lead by A/Prof David Seminowicz (see more information here).

PREDICT Publications

Seminowicz DA, Bilska K, Chowdhury NS, Skippen P, Millard SK, Chiang A, Chen S, Furman AJ, & Schabrun SM. (2020). A novel cortical biomarker signature for predicting pain sensitivity: protocol for the PREDICT longitudinal analytical validation study. Pain Reports, 5(4), e833. doi: 10.1097/PR9.0000000000000833

The No Worries Trial

Researchers: Associate Professor Sylvia Gustin, Nell-Norman-Nott, Dr Negin Hesam- Shariati, Dr. Chelsey Wilks (University of Washington).

Emerging evidence has shown that negative emotional states play a key role in the development and maintenance of chronic pain. The No Worries Trial will evaluate the effectiveness of a four-week internet-delivered Dialectical Behaviour Therapy (DBT) skills training to help chronic pain sufferers cope with painful, fearful, worrisome, anxious, and negative thoughts and emotions. Moreover, by having the DBT skills training online it is more accessible to those in remote communities, to those with restricted mobility, and more broadly it adds to the knowledge of internet-delivered therapies at a time when online is increasingly necessary to deliver treatment due to COVID-19.

A Multi-Site Randomized Clinical Trial to Examine the Efficacy and Mechanisms of Immersive Virtual W

Chronic neuropathic pain (NP) can be a debilitating secondary condition for persons with spinal cord injury (SCI) and effective pharmacological and non-pharmacological treatments remain elusive. This project brings together international experts in basic science and clinical approaches to SCI NP for a rigorous multisite randomized clinical trial to examine the efficacy and mechanisms of an advanced interactive virtual reality (VR) walking intervention (VRWalk).

DISCOVER: Discovery of a cortical biomarker signature for pain

Low back pain (LBP) is ranked as the top single cause of disability worldwide. Costs have risen faster than for any other health condition and LBP is now equal to ischemic heart disease, and second only to cancer, as the costliest health condition. Approximately 40% of people who experience acute LBP develop chronic pain. These individuals are unresponsive to treatment, experience high levels of pain, struggle to perform daily tasks and frequently develop psychosocial comorbidities. The enormous scale of the problem is matched only by the mystery that accompanies it: despite decades of research, why some people develop chronic LBP while others do not, remains unknown.

The identification of biomarkers that can predict who will develop chronic LBP is a holy grail of pain research. Our new research has uncovered evidence for a unique biomarker signature that appears to predict i) an individual’s susceptibility to high pain severity, even before pain begins and ii) an individual’s susceptibility to developing chronic LBP following an acute episode. These biomarkers are now undergoing detailed investigation in on-going studies.

UNmaPPed: Understanding the physiology of persistent pain

People in pain move differently. Yet, the biological basis for altered movement in pain is poorly understood. This lack of understanding has led to treatments for persistent pain that target generic symptoms with limited effect. This NHMRC-funded trial is the first to examine how different aspects of the nervous system are altered in pain and how this relates to movement. This information will guide the development of new treatment strategies for persistent pain in future.

UPWaRD: Understanding persistent pain where it resides – in the brain.

Persistent musculoskeletal pain is one of the most significant health issues in the developed world. Termed a ‘Western epidemic’, low back pain is the most common form of persistent musculoskeletal pain and a leading cause of suffering and disability. Despite the enormity of the problem, many current therapies target generic symptoms, not underlying mechanisms, with limited effect. In 2010, the Australian National Pain Summit concluded ‘the management of pain is shockingly inadequate’. This assessment is not surprising given that critical information on the biological changes that underpin persistent low back pain is lacking. The UPWaRD study is a 5-year NHMRC-funded trial that investigates the role of brain plasticity, along with biological changes in the spinal cord, hormonal changes, genetics and stress, in the development of persistent low back pain.

Medicines for Back Pain

Medicines are the most common treatment for back pain. The aim of this program of research is to improve our understanding of the clinical effects of medicines.

Studies currently in progress:

  1. Scoping review of paracetamol, NSAIDs and opioid analgesics for chronic low back pain (led by Matthew K Bagg). The objective of this study is to identify and describe the characteristics of available clinical trials of commonly used analgesic medicines for chronic low back pain. This information will inform the design and conduct of other studies in the research program.
  2. Paracetamol, NSAIDs and opioid analgesics for chronic low back pain: a network meta-analysis (led by Matthew K Bagg). The objective of this study is to produce information about the clinical effects of available analgesic medicines for chronic low back pain. This information will be available in a Cochrane review to assist clinical prescription of medicines. The protocol is published and available here.
  3. Prescribing practices of medicines for adults with low back pain: a systematic review (led by Michael Wewege). The objective of this study is to determine how different medicines are prescribed to adults with low back pain and how this differs across countries. The protocol for this study is being developed.
  4. Analgesic medicines for adults with low back pain: a network meta-analysis (led by Michael Wewege). The objective of this study is to evaluate the comparative effectiveness of a range of analgesic medicines for adults across different classifications of low back pain. The protocol for this study has been submitted for publication.
  5. Muscle relaxant medicines for low back pain: a systematic review and meta-analysis (led by Aidan Cashin and Thiago Folly). The objective of this study is to determine the effectiveness and tolerability of muscle relaxant medicines for adults with low back pain. The protocol is available here.
  6. Novel biologic medicines for low back pain: a systematic review and meta-analysis (led by Rodrigo Rizzo). The objective of this study is to determine the effectiveness and tolerability of novel biologic medicines for adults with low back pain. The protocol is available here.

Completed studies:

  1. Evaluation of the impact of unpublished data from clinical trial registries on the effects of medicines for low back pain (led by Matthew Bagg). The objective of this study was to evaluate whether there is a difference between clinical trial data that are published and those that are not published. The findings are published in the Journal of Clinical Epidemiology.
  2. Antidepressant medicines for low back pain: a systematic review and meta-analysis (led by Michael Ferraro). The objective of this study was to determine the effectiveness and tolerability of antidepressant medicines for adults with low back pain. The findings have been submitted for publication. The protocol is available here.

Medicines for Back Pain – Publications:

  • Bagg MK, McLachlan AJ, Maher CG, Kamper SJ, Williams CM, Henschke N, Wand BM, Moseley GL, Hübscher M, O’Connell NE, van Tulder MW, Nikolakopoulou A, McAuley JH. (2018). Paracetamol, NSAIDS and opioid analgesics for chronic low back pain: a network meta-analysis [Protocol]. Cochrane Database of Systematic Reviews, Issue 6. doi: 10.1002/14651858.CD013045. PMCID: PMC6513465
  • Bagg MK, O’Hagan E, Zahara P, Wand BM, Hübscher M, Moseley GL, McAuley JH. (2020). Reviews may overestimate the effectiveness of medicines for back pain: systematic review and meta-analysis. Journal of Clinical Epidemiology. doi: 10.1016/ j.jclinepi.2019.12.006. PMID: 31816418

Medicines for Back Pain – Registrations of Study Protocols:

  • Folly T, Bagg MK, Wewege M, Ferraro MC, Schabrun S, Gustin SM, Day R, McAuley JH. (2019) UMbRELLA: Understanding efficacy and safety of Muscle RELaxant medicines for Low back pain – systematic Literature review and meta-Analysis (protocol).Open Science Framework, available at:
  • Rizzo RN, Bagg MK, Ferraro MC, Wewege M, Cashin A, Leake HB, O’Hagan E, Jones M, McAuley JH. (2020). Efficacy and safety of medicines targeting neurotrophic factors in the management of low back pain: protocol for a systematic review and meta-analysis. Open Science Framework, available at:
  • Ferraro MC, Bagg MK, McAuley JH. (2019). RADICAL: Systematic Review of Anti-Depressant Medicines if Considered Analgesics for Low Back Pain (protocol). Open Science Framework, available at:

Social Media for Low Back Pain

Social media is a potentially powerful tool to provide a message of education and reassurance to the general public about low back pain. This project will use social media to educate the general public about low back pain and promote self-management.

The project involves three stages. Firstly, we will conduct a content analysis to gain an insight into social media users’ perceptions and understanding about low back pain. This could determine whether social media could serve as an educational tool through which accurate information related to low back pain could be disseminated to the public.

Second, a recent Delphi survey of 150 low back pain researchers identified 30 key messages considered to be important for the general public to know about LBP. These statements provide evidence-based information on the diagnosis, prognosis and management of LBP and are intended to educate, reassure and promote self-management. We will investigate the attitude of the general public towards these messages.

Third, working in conjunction with a media company Y&R, we will design and test a social media campaign to encourage self-management for people with low back pain.


For people with back pain who are having trouble with their sleep. We are testing whether a simple sleep tablet will help people reduce their pain and sleep better.

RESOLVE Trial for Chronic Low Back Pain

For people with long term back pain that is not getting better. We are testing two pain treatment programs that target the brain, for people with chronic low back pain.

Patient Education to PREVENT Chronic Low Back Pain

For people with a new low back pain episode. We are testing early intervention to reduce the risk of developing chronic low back pain.

The effects of tonic muscle pain on the sympathetic and somatic motor systems

Chronic pain, defined as pain lasting for >3 months, typically develops from injuries to deep tissues such as muscle, yet little is known about how long-lasting pain affects a person’s blood pressure or capacity to control their muscles. This project assesses the effects of tonic muscle pain on sympathetic nerve activity and stretch sensitivity of muscle spindles.

What else is happening in Pain research at NeuRA?