Written by Professor David Finn, Principal Investigator and Founding Co-Director, Centre for Pain Research, NUI Galway, Mary Hopkins, PhD Researcher, Stephanie Bourke, PhD Researcher, NUI Galway
Chronic pain is a complex condition that imposes a huge burden on patients, and the healthcare system. It is estimated that between 13% and 36% of the Irish population are affected by Chronic Pain (Purcell et al., 2022). The Prevalence, Impact and Cost of Chronic Pain (PRIME) study published in 2012 highlighted the cost of chronic pain in Ireland (Raftery et al., 2011). The mean cost of this condition per patient per year at that time was estimated to be just under €6000. For all chronic pain patients in Ireland this amounted to over €5bn, which is largely in line with other European countries (around 1.5-3% GDP per country). Treating chronic pain and the socioeconomic problems that it presents is not an easy challenge. There is a severe shortage of specialist pain services generally in Ireland, and specifically there is a shortage of multidisciplinary pain management programmes which contributes to the challenge of delivering a multimodal treatment approach.
Furthermore chronic pain is highly comorbid with anxiety and depression. According to the PRIME study, clinically significant depression was nearly 5 times more common in patients with chronic pain (Raftery et al., 2011). There is a need to understand the influence of stress, anxiety and depression on chronic pain.
Furthermore there is a need for more research into the different presentations of pain between males and females. Chronic pain is more prevalent in females, which is often linked to the increased occurrence in females of comorbid conditions like arthritis, fibromyalgia, migraine and TMD (temporomandibular disorder). The relative lack of research involving females is now starting to be redressed in order to clarify and better understand the sex differences that exist at the neurobiological level in chronic pain.
Treatments for chronic pain have advanced in looking to a more holistic way of treating the individual. However there will always be a demand for pharmacological options as 1st line treatments. The rise of the opioid crisis in North America has highlighted the need for treatments with less addictive properties. Furthermore many other treatments such NSAIDs are not without risk e.g. gastrointestinal side effects. 70% of patients with chronic pain say their medication is unsatisfactory at treating their pain some of the time, and 40% say some medications are always inadequate all the time (Breivik et al., 2006 ). So it is clear that there is an urgent need for more efficacious treatments that have fewer severe side effects. The National University of Ireland (NUI) Galway’s Centre for Pain Research, established in 2007, was born of the need to discover the most novel and cutting edge therapies of the future. It hopes to bring together, academics, basic scientists, clinicians and researchers from all corners of the healthcare system to tackle the need for better patient outcomes.
Professor David Finn is a founding Co- Director of the Centre for Pain Research. His research focuses on the basic sciences and translational clinical research on pain. His research group focuses on investigating the body’s own endogenous cannabinoids, called endocannabinoids, which are produced in the brain and other tissues. Endocannabinoids have been shown to change in response to pain, stress and other causes. They present a novel target for discovering biomarkers of pain, and also as a novel therapeutic target.
Medicinal cannabis and cannabis based medicines has been a novel research area that has exploded in the last 20-30 years. Cannabis sativa has been cultivated and used for recreational and medicinal purposes for at least 5000 years (Crocq, 2020 ). However, it is only in the last 20-30 years that we have observed research progressing in this field, and this is largely to do with the scientific identification of receptors and ligands within the endocannabinoid system. Knowledge of this physiological system has allowed for the development of drugs that can target our own endocannabinoid system and also gives us a better understanding on the use of medicinal cannabis and cannabis based medicines as therapeutics. Research in the Finn group looks at the relationship between pain, comorbid conditions and the endocannabinoid system as a potential biomarker and a novel therapeutic target.
One of the projects in Prof Finn’s group, funded by the Irish Research Council, is looking at how the endocannabinoid system changes in chronic low back pain. Chronic low back pain (LBP) is a serious medical and socioeconomic problem, and a leading contributor to disability. The point prevalence of LBP in 2017 was estimated to be about 7.5% of the global population, or around 577 million people (Wu et al., 2020). Estimates predict an 80% probability of having LBP at some stage of life, and that 19% of the Irish population have experienced some LBP over the last year (Andersson, 1999; Raftery et al., 2011). In 2015, the Healthy Ireland national report showed that back pain is the most common health condition reported in Ireland, ahead of the well-recognised conditions of high blood pressure, heart disease, asthma, diabetes and depression ([DoH], Department of Health, 2015). Treating back pain accounts for about 25% of doctor’s visits.
Current treatments for low back pain range from pharmacological (nonsteroidal anti-inflammatory drugs, opioids, gabapentinoids, etc.) to highly invasive medical procedures such as spine fusion and artificial disk replacement. However there is need for a greater understanding of the mechanisms of how people develop ongoing LBP, and novel treatments which have greater efficacy and fewer side effects associated with their use.
We know that there can be changes in the endocannabinoid system in patients with LBP. There is evidence for alterations in blood levels of these molecules in healthy participants versus patients in pain (Degenhardt et al., 2007; Woodhams et al., 2017), and there are changes seen in the expression of genes and underlying gene polymorphisms between patients who report LBP and healthy controls (Starkweather et al., 2016; Ramesh et al., 2018). Consequently this project aims to use a pre-clinical model of LBP, which involves the degeneration of intervertebral discs in the spine to mimic the clinical phenotype. This model will help to understand the underlying mechanistic molecular and biochemical pathways that are involved in the changes we see in the endocannabinoid system in LBP.
Running in parallel to this work is an ongoing clinical study involving healthy participants, and those who suffer from acute and chronic LBP. This study will investigate whether male and female human patients with LBP have altered pain sensitivity associated with changes in endocannabinoid levels. The findings from this study will advance understanding of the nuances of the clinical presentation of LBP and how the endocannabinoid system is changing in LBP. In this clinical study participants will be asked about how have been experiencing pain, their comorbidities, their anxiety and fear related to their pain, their ongoing therapies and how this affects their daily quality of life. Depending on how long they have had the pain, participants will be assigned to either acute or chronic LBP groups for research purposes. Then participants will have some special tests to see how sensitive they are to stimulo on their skin such as heat, cold and pressure. This will use a state of the art quantitative sensory testing equipment. During this session two blood and saliva samples will be taken. The research will be carried out at Clinical Research Facility in University Hospital Galway.
The LBP project overall will look at a translational approach to examine the novel hypothesis that a reduction in endocannabinoid signalling underpins the development and maintenance of chronic LBP and that altered pain sensitivity in patients is associated with alterations in blood endocannabinoid levels. By clarifying the neurobiological mechanisms contributing to chronic LBP in the pre-clinical model, the project aims to pave the way for the development of endocannabinoids as potential novel diagnostic biomarkers and/or therapeutic targets for chronic LBP.
Stress, anxiety and depression are frequently found to co-occur in patients with chronic pain conditions. Stress has a complex effect on pain, it can enhance or dampen our sensation of pain depending on the nature of the stressor, the duration for which it lasts and the intensity of the stressor itself. Recent findings suggest that anxiety may play a significant role in how individuals respond to pain and may influence the significant differences between male and female pain sensitivity (Thibodeau et al., 2013). Gender differences in stress reactivity may be involved in the differences observed in pain sensitivity and assessment has relied primarily on measuring physiological responses to acute stressors in laboratory settings, including Hypothalamic-Pituitary- Adrenal (HPA) axis and sympathetic nervous system activity. HPA response patterns differ markedly between males and females. There is also now a substantial volume of evidence that endocannabinoids, are involved in the control of both anxiety and pain sensitivity. Studies have shown that concentrations of blood endocannabinoid levels correlate with emotional variables such as depression and anxiety (Hill et al., 2008 ). Preclinical literature on stress response, pain sensitivity and endocannabinoid levels, indicates a possible relationship that is yet to be thoroughly investigated in humans.
Therefore, the Finn group are investigating the relationship between anxiety, pain and endocannabinoids in healthy human participants in order to better understand the impact of stress on pain. Specifically, they investigate the extent to which anxiety and circulating endocannabinoid levels predict pain sensitivity and modulation of pain by stress in both healthy male and female human participants using methodologies that allow us to quantify pain sensitivity in humans. This research, funded by the Irish Research Council, will significantly advance our understanding of the modulation of pain by stress and anxiety in both sexes and will determine the extent to which the endocannabinoid system plays a role.
Ultimately the group at NUI Galway aim to investigate the role that endocannabinoids play in clinical pain states. The results from their clinical studies will inform the development of endocannabinoids as potential novel biomarkers and/ or therapeutic targets for pain and its comorbidity with anxiety.
References available on request
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