Chronic pain, which typically lasts longer than three months, is a major health problem, affecting 20–30% of the world’s population, according to the US Centers for Disease Control and Prevention; think whiplash or tennis elbow, the pain of which can persist long after the initial injury. Some health economists have estimated chronic pain results in $635bn in direct and indirect annual costs in the US alone.
Typically, exhausted and often depressed patients with chronic pain have a poor quality of life. What exacerbates their predicament is that more often than not doctors can’t find any cause for the pain. And because they suffer from something that can’t be seen, patients often feel they are not believed.
‘The fact that many chronic pain patients have little or no sign of physical damage is certainly problematic and affects a large number of people,’ says Marco Loggia, assistant professor of radiology at Harvard Medical School, US, and associate director of the Center for Integrative Pain NeuroImaging (CiPNI) at Massachusetts General Hospital, Boston, US. ‘Many patients with common pain disorders, such as chronic low back pain or osteoarthritis, don’t show any physical signs of disease [on X-rays or magnetic resonance imaging (MRIs), for example]. Whenever we do see any physical changes, they are often not predictive of the levels of pain or disability [reported by patients].’
Loggia adds that lacking an objective marker for pain can prevent patients in real need from accessing appropriate treatment; vice versa, it can allow some individuals with no pain whatsoever to access drugs to use merely for recreational purposes. ‘Moreover, when we can’t see “anything wrong” in somebody who genuinely is in pain, it also means that we don’t really know what mechanisms need to be treated in that patient,’ he says.
Relief in sight
However, there is some good news. Recently, researchers in Sweden have shown that chronic pain-generating processes can be visualised. ‘This hasn’t been feasible before. By injecting substances into the body and then taking pictures using a PET [positron emission tomography] camera, we can now reveal pain processes that can’t be seen in ordinary X-ray, CT [X-ray computed tomography] or MRI images,’ says Torsten Gordh, Sweden’s first professor of clinical pain research, and chief physician at the Multidisciplinary Pain Clinic, Uppsala University Hospital. ‘Chronic pain is no longer an invisible disease.’
Gordh’s team and close collaborators at the PET centre at Uppsala University Hospital presented their latest findings at the AAAS international scientific conference in San Jose, US, in February 2015. Using the tracer C11D-deprenyl, a potential marker for inflammation, Gordh and his colleagues showed that on PET scans, for most whiplash patients suffering from chronic pain, there is a significant concentration of deprenyl in the neck – depicted as bright areas on the scan – particularly in regions implicated in whiplash injuries and at which patients say they hurt (see images, top right).1 In contrast, there are no such areas on the scans of pain-free patients.
PET and tracers
A PET scanner produces a 3D image of processes in the body by detecting γ-rays, resulting from the emission of positrons from a radioactive tracer. The tracer, which is attached to a biologically active molecule – in this case, D-deprenyl – has a short half-life and is injected into the body where it concentrates at certain points, depending on what the biologically active molecule is. A computer constructs a 3D image of tracer concentration.
Deprenyl is a selective, irreversible monoamine oxidase (MAO) B inhibitor widely used in the treatment of Parkinson’s disease. That it could be a marker for inflammation in peripheral tissue was an accidental discovery about 10–15 years ago, says Gordh. Deprenyl was known to accumulate in cerebral scars and was being studied in the imaging of epilepsy patients, when researchers noticed that the scans lit up in additional, unexpected places. The deprenyl accumulated in inflamed joints of those patients who were also suffering from pain in those places. This led the researchers to find out whether inflammation could be detected through the uptake of deprenyl tracers.
Following work showing that deprenyl accumulates in the knees of patients with rheumatoid arthritis2, Gordh and colleagues found that painful processes in the periphery can indeed be visualised and measured using PET and that D-deprenyl is a promising tracer.1
Since then, other groups have investigated the use of PET to create images of pain processes. For example, Magnus Peterson and colleagues, also at Uppsala University, have studied the pain connected with tennis elbow, which patients often report starts at a point in the elbow and radiates down the forearm. There is usually no sign of inflammation in those areas but, using the neuropeptide substance P as a tracer for the signal receptor NK1, the availability of which changes in the central nervous system (CNS) in response to pain, the researchers showed that painful processes in the arm could be visualised (see bottom image, right).3
Gordh and colleagues have also found distinct uptake of deprenyl on PET scans of once-sprained ankles of patients with persistent ankle pain. ‘We believe chronic pain processes can be visualised this way
if they are connected to some degree of inflammation,’ says Gordh. The exact binding site of deprenyl is unknown.
A new diagnostic tool
Visualising once-invisible peripheral pain processes using PET could provide a new diagnostic tool for chronic pain. ‘For the doctor, it gives a better pain diagnosis and better understanding of pain pathophysiology that could, in the long run, guide effective targeted treatment with different kinds of anti-inflammatories. For patients, such scans support what the patient is claiming, usually for the first time,’ says Gordh.
‘Certainly an imaging test capable of pinpointing some pathological alterations could impact both patients and physicians. It could aid with diagnosis and, in some cases, guide treatments,’ agrees Loggia.
Additionally, for scientists, the findings give a clue to the peripheral driving processes of chronic pain and may help shift the focus of research towards peripheral signalling as a driver of over-sensitivity in the nervous system, says Gordh.
Until now, it has generally been thought that the acute inflammation that follows peripheral tissue damage goes away – that without obvious changes in peripheral tissue there can be no ongoing inflammation year after year. This has led scientists to focus on processes in the CNS – the brain and spinal cord – as explanations for chronic pain. ‘As a pain researcher, my view is that both [CNS and peripheral] are involved, cooperating,’ says Gordh.
‘In the past few years, we have started to realise that when nothing seems wrong ‘peripherally’ then maybe we should start looking for alterations in the central nervous system, [which,] in fact, has dramatic modulatory effects on pain,’ says Loggia. His team’s most recent study using PET has shown for the first time that a set of non-neural cells, called glia, are ‘activated’ in the brain of patients with chronic low back pain.4
‘Functional imaging techniques of the brain have advanced to the point that we can tell with a reasonable degree of accuracy whether someone is in pain and even how intense the pain may be,’ says Daniel Clauw, professor of anaesthesiology, medicine (rheumatology) and psychiatry, and director of the Chronic Pain and Fatigue Research Center at the University of Michigan, US. ‘[Gordh’s] study suggests that new functional imaging techniques of peripheral tissues might hold similar promise.’
PET imaging with D-deprenyl, however, is currently used only in research projects and is not yet routine in the clinic. Every scan costs around £1500 and the tracer molecules are custom-made just before a trial.
Gordh’s team is expected to publish its latest work on PET imaging of chronic pain in the ankle and neck later in 2015, and is also investigating the imaging of pain processes in fibromyalgia and endometriosis.
1 PLoS One, 2011, doi: 10.1371/journal.pone.0019182.
2 T. Danfors et al, Scand. J. Rheumatol., 1997, 26(1), 43.
3 PLoS One, 2013, doi: 10.1371/journal.pone.0075859.
4 Brain, 2015, doi: 10.1093/brain/awu377.
Top: D-Deprenyl uptake in a representative healthy control (left) and a whiplash patient (right)1
Emma Dorey is a freelance science writer based in Brighton, UK