Pain and analgesics
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2002 – 2005 Dr Hadwen Trust Research Fellowship: Understanding pain and its alleviation using fMRI with human subjectsProf I Tracey, Prof P Matthews, Dr R Wise and Dr J BrooksCentre for Functional Magnetic Resonance Imaging of the Brain, Oxford University |
Professor Irene Tracey is the Director and co-founder of the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), Nuffield Professor of Anaesthetic Science, and a Fellow of Medicine at Pembroke College. Her research interests are the neural mechanisms of pain perception and its modulation in health and disease. Her multidisciplinary Pain Imaging Neuroscience group has contributed significantly to a better understanding of pain perception and its relief within the human nervous system.
Professor Paul Matthews was Director of the Oxford FMRIB at the start of this project. He is now Professor of Clinical Neurosciences at Imperial College, London, and (honorary) MRC Clinical Research Professor at Oxford University.
Dr Richard Wise was supported by a postdoctoral Dr Hadwen Trust research fellowship for the initial part of this project. Dr Wise’s research interests include the development of fMRI methods for human pharmacological imaging studies, and he is now fMRI Director at the Cardiff University Brain Research Imaging Centre.
Dr Jonathan Brooks was supported by a Dr Hadwen Trust research fellowship for the latter part of this project. Dr Brooks is a member of the Oxford Pain Imaging Neuroscience group and has a particular interest in spinal cord imaging.
Chronic pain is one of the largest medical health problems in the developed world, affecting 20% of the adult population. Statistics may be even worse for the undeveloped world, but data are currently unavailable. Chronic pain creates an enormous emotional and financial burden to sufferers, carers and society in general, and innovative methods are needed to combat this massive and growing problem.
Pain is a subjective experience. How a painful (nociceptive) stimulus is experienced is influenced by cultural, psychological, pathological and cognitive factors, and may be interpreted differently by different individuals. Traditionally pain and pain alleviating drugs have been studied in animals, although this enables the study of only the crudest behavioural manifestations of pain.
Animals are used extensively in the development and testing of painkilling drugs, but they have failed to provide effective treatment, especially for chronic pain. To really understand human pain, we must understand how painful stimuli are processed in the human brain. Until recently it was difficult to obtain reliable objective information from healthy volunteers and patients regarding their subjective experience of pain. However the development of functional magnetic resonance imaging (fMRI) has made it possible to safely and non-invasively monitor activity in the human brain in response to painful stimuli.
The Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB) is an internationally renowned neuroimaging laboratory that specialises in cutting-edge developments in MR physics and image analysis, and their application to the study of pain, stroke, vision and other areas of neuroscience research. A three-year grant from the Dr Hadwen Trust supported research at the FMRIB that produced major new insights into human pain without recourse to animal experiments, and furthered the development of methodology for spinal cord imaging.
Firstly, fMRI was used to reveal how the human brain’s response to pain is altered by remifentanil, a painkiller similar to morphine [1]. Further work improved the sensitivity of the technique, making it possible to not only identify areas of the brain affected, but also to measure within specific brain regions how long a painkiller takes to have an effect on brain activity and how long the effect lasts [2]. These are important aspects of understanding how painkilling drugs act and make fMRI a potentially useful tool for assessing novel analgesics.
A novel high-resolution fMRI technique developed at the FMRIB Centre was used to map heat/pain pathways of the dorsal posterior insula cortex. Human volunteers received mildly painful stimuli at three distinct locations on the right side (foot, hand and face) and results demonstrated that connections to the posterior dorsal insula are arranged somatotropically [3]. This finding has relevance to the current theories of neuroanatomical arrangement of pain sensation in humans, and could have implications for studying patients with chronic pain.
Significant progress was made in the development of methods for extending fMRI to the spinal cord, a relatively new and technically demanding process. The spinal cord is important in processing pain and this imaging development will allow non-invasive investigation of human spinal function and the changes that are thought to underlie some clinical pain conditions [8]. It could also have wider applications for the study of pain processing and conditions such as multiple sclerosis.
The Dr Hadwen Trust research fellow also contributed to various other human pain research projects, including the development of new methods of combining fMRI with EEG to study pain related brain activity [4]; the use of heat/capsaicin sensitisation pain models in healthy human subjects to mimic neuropathic pain (pain caused by nerve damage) [5]; methodological improvements to fMRI to improve its suitability for clinical studies and drug trials [6]; and studies of allodynic pain (pain caused by normally non-painful stimuli) in patients [7].
The range of projects undertaken at the Oxford FMRIB Centre demonstrates the potential for investigating clinical pain instead of conducting animal experiments. Pain research with human volunteers can help to replace animal experiments and importantly yield data that are directly relevant to humans [9].
Summary
- Pain is a subjective experience and chronic pain is a huge medical problem affecting many people.
- Animals have been extensively used to study pain but provide only limited information. We can only find innovative and effective new ways of tackling human pain by understanding how the human brain processes pain.
- A grant from the Dr Hadwen Trust funded cutting-edge research at the internationally renowned Oxford FMRIB Centre to study pain and analgesics in human volunteers as an alternative to animal experiments.
- Our research fellow helped to develop fMRI methods for human pharmacological imaging studies, and provided new information about how the painkilling drug remifentanil affects the human brain’s response to pain.
- Pain pathways in an area of the human brain called the dorsal posterior insula were mapped, with implications for research into chronic pain conditions.
- Significant developments were made to methods for applying fMRI to the spinal cord, providing a novel and potentially important new non-invasive tool for studying pain processing in humans.
Publications
- Wise RG, Rogers R, Painter D et al (2002). Combining fMRI with a pharmacokinetic model to determine which brain areas activated by painful stimulation are specifically modulated by remifentanil. Neuroimage 16:999-1014.
PubMed Link - Wise RG, Williams P & Tracey I (2004). Using fMRI to quantify the time dependence of remifentanil analgesia in the human brain. Neuropsychopharmacology 29:626-35.
PubMed Link - Brooks JC, Zambreanu L, Godinez A et al (2005). Somatotopic organisation of the human insula to painful heat studied with high resolution functional imaging. Neuroimage 27:201-9.
PubMed Link - Iannetti GD, Niazy RK, Wise RG et al (2005). Simultaneous recording of laser-evoked brain potentials and continuous, high-field functional magnetic resonance imaging in humans. NeuroImage 28:708-719.
PubMed Link - Zambreanu L, Wise RG, Brooks JC et al (2005). A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging. Pain 114:397-407.
PubMed Link - Tjandra T, Brooks JCW, Figueiredo P et al (2005). Quantitative assessment of the reproducibility of functional activation measured with BOLD and MR perfusion imaging: Implications for clinical trial design. NeuroImage 27:393-401.
PubMed Link - Schweinhardt P, Glynn C, Brooks J et al (2006). An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients. Neuroimage 32:256-265
PubMed Link - Brooks JC & Tracey I (2005). From nociception to pain perception: imaging the spinal and supraspinal pathways. J Anat. 207:19-33.
PubMed Link - Langley CK, Aziz Q, Bountra C et al (2008). Volunteer studies in pain research – Opportunities and challenges to replace animal experiments. The report and recommendations of a Focus on Alternatives workshop. Neuroimage 42:467-473.
PubMed Link